Purinergic Receptors in Special Scences

8/8/2019 Purinergic Receptors in Special Scences

1/14

Purinergic signaling in special sensesGary D. Housley1, Andreas Bringmann2 and Andreas Reichenbach3

1 Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, Faculty of Medicine,

University of New South Wales, Sydney, NSW 2052, Australia2 Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrae 10-14, D-04103 Leipzig,Germany3 Paul Flechsig Institute of Brain Research, Faculty of Medicine, University of Leipzig, Jahnallee 59, D-04109 Leipzig, Germany

We consider the impact of purinergic signaling on the

physiology of the special senses of vision, smell, taste

and hearing. Purines (particularly ATP and adenosine)

act as neurotransmitters, gliotransmitters and paracrine

factors in the sensory retina, nasal olfactory epithelium,

taste buds and cochlea. The associated purinergic re-

ceptor signaling underpins the sensory transduction and

information coding in these sense organs. The P2 and P1

receptors mediate fast transmission of sensory signalsand have modulatory roles in the regulation of synaptic

transmitter release, for example in the adaptation to

sensory overstimulation. Purinergic signaling regulates

bidirectional neuronglia interactions and is involved in

the control of blood supply, extracellular ion homeosta-

sis and the turnover of sensory epithelia by modulating

apoptosis and progenitor proliferation. Purinergic sig-

naling is an important player in pathophysiological pro-

cesses in sensory tissues, and has both detrimental (pro-

apoptotic) and supportive (e.g. initiation of cytoprotec-

tive stress-signaling cascades) effects.

Introduction

The past two decades were witness to a rapid accumulation

of data showing that purinergic signaling is an essential

and crucial factor throughout the vertebrate nervous sys-

tem. Purines and pyrimidines acting at purinergic P1 and

P2 receptors are extracellular signaling molecules involved

in nearly every aspect of development, pathophysiology,

neurotransmission and neuromodulation [1,2]. Adenosine

(P1) receptors are subdivided into four subtypes (A1, A2A,

A2B and A3), all of which couple to G proteins. P2 receptors

(recognizing primarily adenine and uracil tri- and dinu-

cleotides) comprise two families: ionotropic P2X and G-

protein-coupled P2Y receptors. P2X receptors (which

represent ATP-gated ion channels) are subdivided into

seven subtypes (P2X1 to P2X7); P2Y receptors compriseat least eight subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11,

P2Y12, P2Y13 and P2Y14). These subtypes differ in their

molecular structure and selectivities to agonists and

antagonists [1]. P2X receptors contribute to fast excitatory

synaptic transmission and also act presynaptically to

modulate neurotransmitter release, whereas P2Y recep-

tors are involved in neuromodulation and neuronglia

interactions. Adenosine has a key role in the regulation

of tissue oxygenation, neuronal firing, neurotransmitter

release and cytoprotective responses. ATP is released as a

cotransmitter via vesicle-mediated exocytosis from synap-

tic terminals, and from non-neuronal cells by secretion of

vesicles or calcium-independent mechanisms via plasma-

membrane nucleotide-transport proteins, connexin or pan-

nexin hemichannels, anion channels and other processes

[2]. Adenosine can be released by nucleoside transporters

or is formed extracellularly from ATP by ecto-nucleoti-

dases [2]. Degradation of nucleotides by ecto-nucleotidases

also provides rapid termination of purinergic signaling [2].

As in the brain, purinergic receptors are abundant in thetissues of special senses. Here, we aim to critically evaluate

what is presently known (and proposed) about the path-

ways and roles of purinergic signaling in the special sense

organs of vision, olfaction, taste and hearing. These can be

part of the central nervous system such as the retina or of

the peripheral nervous system such as the inner ear, the

olfactory epithelium and taste buds. Moreover, the charac-

teristics of the stimulus in addition to the degree of local

information processing differ greatly among the senses.

Joint review of purinergic signaling in these sensory sys-

tems provides an opportunity to consider which roles are

adaptations to specific purposes and which are general

features of the nervous tissue.

Vision

In the sensory retina, purines are tonically released in

darkness; the release increases with neuronal activity [3].

ATP is liberated from neurons in a Ca2+-dependent man-

ner [3,4] and from glial and pigment epithelial cells by

Ca2+-independent mechanisms [58]. Adenosine might be

released via nucleoside transporters by ganglion and glial

cells [8], and it can be formed enzymatically in the extra-

cellular space from ATP [911]. Ecto-nucleotidases have

been localized to both plexiform (synaptic) layers [1214].

Neurotransmission and neuromodulation

In the retina, photoreceptors, most neurons, glial cells, the

microvasculature and pigment epithelial cells express P1

and P2 receptors (Table 1). ATP is likely to contribute to

fast excitatory neurotransmission by activation of P2X

receptors and has a potential neuromodulatory role acting

at P2Y receptors localized to neuronal and supportive cells

(Figure 1; Table 1). However, the role of purines in reg-

ulating retinal function is not well determined. Under-

standing the function of ATP in the retina is also

complicated by species differences. It has been suggested

that various P2X receptor subtypes are differentially

involved in specific circuits within the retina; P2X7 might

preferentially modulate signal transmission in the rod

Review

Corresponding author: Housley, G.D. ([email protected]).

128 0166-2236/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.01.001 Available online 18 February 2009
mailto:[email protected]://dx.doi.org/10.1016/j.tins.2009.01.001http://dx.doi.org/10.1016/j.tins.2009.01.001mailto:[email protected]


2/14

Table 1. Expression of purinergic receptor subtypes in different cell types of the sensory retina a

Receptor subtypes Species Localization and functional activity Refs

Photoreceptors

A1, A2 Salamanderb,c Inhibition of L-type Ca2+ currents and glutamate release from rods [21]

A2 Rabbitd and moused Inner and outer segments of photoreceptors [140]

A2 Teleostse Induction of cone elongation in dark; increase in cAMP level [141]

A2A Salamanderf Inhibition of opsin mRNA expression in rods at night; increase

in cAMP level

[142]

P2X2 Ratf,g Somata and outer segments of photoreceptors [143]

P2X7

Rat and marmosetg,h,i Increase in the amplitude of the ERG a-wave [12,16]

P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j, rabbitf and

macaquefInner segments of photoreceptors [144146]

Bipolar cells

A1 Ratc Suppression of NMDA-mediated currents [26]

P2X3, P2X 4, P2X 5 Ratj Not determined [147]

P2Y1, P2Y2, P2Y4, P2Y6 Ratg,h,j Not determined [148,149]

Retinal ganglion cells

A1, A2A, A3 Ratf and mousek Not determined [150,151]

A1 Ratb,c Inhibition of voltage-dependent Ca2+ channels and of the

glutamate-induced increase in cytosolic Ca2+; activation of K+ channels;

decrease in the spike activity

[9,10,23]

A1 Salamander2 Inhibition of N-type Ca2+ channels [22]

A3 Ratb Inhibition of P2X7-receptor-mediated Ca

2+ rise and ganglion cell death [58]

P2X2, P2X3, P2X4,

P2X5, P2X 7

Ratf,g,j Not determined [15,143,152154]

P2X7Ratb,g Sustained increase in cytosolic Ca2+; activation of L-type Ca2+ channels

and of caspases; cell death

[57]

P2X7 Mouseg,j Not determined [155]

P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j Not determined [145,148]

Amacrine cells

A1 Chickb,e and rabbite Inhibition of N-type Ca2+ channels and PLC; inhibition of ACh release [4,24,25]

P2X1, P2X2, P2X3,

P2X5, P2X7

Ratg,h and mouse6 Not determined [13,15,156,157]

P2X2 Mouseg Inhibition of ACh release from OFF cholinergic amacrines [17,18]

P2X7 Ratg,h,j Not determined [16,154]

Horizontal cells

P2X7 Monkeyg ratg,h Not determined [16,153]

Interplexiform cells

P2X3 Ratg,h Not determined [13]

Retinal astrocytes and Muller cells

A1 Rate Inhibition of osmotic cell swelling; activation of K+ and Cl channels [14,31,158]

A1, A2A, A2B Rat

b,c

Potentiation of light-evoked Ca

2+

responses [20]A2 Rat

b Elicitation of Ca2+ waves [159]

P2X7 Humanb,c Ca2+ influx; cell depolarization; activation of BK channels; stimulation

of cell proliferation

[47,160]

P2Y1, P2Y2, P2Y4,

P2Y6, P2Y11, P2Y13

Salamanderb Elicitation of Ca2+ waves [161,162]

P2Y1, P2Y2, P2Y4, P2Y6 Ratb,j Elicitation of Ca2+ responses [8,148,159,164]

P2Y1 Rate Inhibition of osmotic cell swelling; stimulation of transporter-mediated

release of adenosine

[8,31]

P2Y1, P2Y2, P2Y4, P2Y6 Humanb,c,g,j Elicitation of Ca2+ responses; activation of BK channels [163,165]

Retinal microglia

P2X7 Rate Formation of transmembrane pores; induction of apoptosis; release

of inflammatory cytokines (e.g. TNFa, interleukin-1b)

[166,167]

P2Y2, P2Y4 Rate Stimulation of cell proliferation [167]

P2Y1 Rabbite Retraction of cell processes [168]

Pericytes of retinal microvasculature

A1, A2A Ratc

Hyperpolarization of pericytes; opening of KATP channels [30]P2X7, P2Y4 Rat

b,c Pericyte depolarization and contraction; Ca2+ responses [169]

P2X7, P2Y4 Ratb,c P2X7: formation of transmembrane pores; activation of

voltage-dependent Ca2+ channels and lethal Ca2+ influx

[170]

P2Y4: inhibition of P2X7 pore formation

Retinal pigment epithelium

A1, A 2 Humanb,e Potentiation of ATP-evoked Ca2+ responses [171]

A2 Pige Increase in cAMP level [172]

A2B Rate Inhibition of phagocytosis of outer segments; increase in cAMP level [173]

P2X, P2Y Ratb,c P2X: nonselective cation conductance [174]

P2Y: release of Ca2+ from internal stores; activation of BK currents

P2Y1, P2Y2, P2Y4,

P2Y6, P2Y12

Humanb,j,l Ca2+ responses [175]

P2Y2 Cowb,c, humanb,c

and rabbite,fCa2+-dependent increase in Cl conductance and decrease in K+

conductance; stimulation of the transcellular fluid transport

[36,37,176]

Review Trends in Neurosciences Vol.32 No.3

129


3/14

pathway and P2X2 in the cone pathway[12,15,16]. P2X7 is

expressed by nearly every type of retinal neuron (Table 1).

In the rat retina, P2X7 was localized to photoreceptor

terminals near the ribbon synapse, to horizontal cells

invaginating the photoreceptor terminals and to amacrine

cells that provide synaptic input onto the rod bipolar

terminal [12,16]. P2X7 receptor activation results in an

increase of the photoreceptor-derived a-wave of the elec-troretinogram and in transient reduction of the photo-

receptor-derived postsynaptic responses [15].

In the mouse retina, ATP might modulate signal pro-

cessing of the ON and OFF pathways in an asymmetrical

manner. The immunohistochemical distribution of dis-

tinct P2X receptor subtypes differs between the ON and

OFF pathways, with a selective enrichment of P2X2 in

OFF cholinergic amacrines [17,18]. Here, ATP increases

g-aminobutyric acid (GABA)ergic inhibitory postsynaptic

currents in OFF but not ON cholinergic amacrines, and

suppresses OFF ganglion cells but activates ON ganglion

cells [17]. In the rat retina, P2X2 is localized to GABA-

ergic amacrine cells (that form synapses with cone but

not rod bipolars) and a population of ganglion cells [15]. Afurther unresolved problem is the source(s) of ATP

involved in synaptic transmission. It has been speculated

that ATP is co-released with GABA from GABAergic

amacrines and horizontal cells [16], with acetylcholine

from cholinergic amacrines [19] and, possibly, from

ganglion cells [20].

Table 1 (Continued)


Developing retina

A2 Ferret, mouseb,g Increase in the spontaneous activity of ganglion and amacrine cells

by stimulation of adenylyl cyclase and PKA activity

[177]

A2A Chicke Increase in the survival of developing retinal neurons; increase

in cAMP level

[178]

P2Y1 Xenopusm Initiation of eye formation; expression of Pax6 and Rx1 [39]

P2Y1 Chicke Stimulation of the proliferation of late progenitors; activation of PLC,

PKC and ERKs

[43,44]

P2Y2, P2Y4 Chickb,e Stimulation of the proliferation of early progenitors [7,40,41]

aAbbreviations: ACh, acetylcholine; BK, Ca2+-activated K+ channels of large conductance; cAMP, cyclic AMP; ERG, electroretinogram; ERK, extracellular signal-regulated

kinase; KATP, ATP-sensitive K+ channels; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

Expression of purinergic receptors was identified by the following methods:bCa2+ imaging; celectrophysiology; dradioligand labeling; epharmacology; fin-situhybridization;gimmunohistochemistry; helectron microscopy; ienzyme histochemistry; jRTPCR; ktransgene expression; lwestern blotting; mreceptor knockdown.

Figure 1. Purinergic signaling in the retina. The following purinergic paths are symbolized by the arrows: (1) modulation of processes of transduction in the photoreceptor

cells; this involves A1 and A2 receptors and several types of P2X and P2Y receptors; the probable agonist sources are glial and/or RPE cells; (2) modulation of signal

processing in the OPL; this involves A1, A2 and P2X7 receptors; the agonist source(s) is unknown; (3) modulation of signal processing in the IPL; this involves A1 and several

types of P2X receptors; the agonist source(s) is unknown; (30) modulation of cholinergic amacrine cells; this involves A1 and P2X2 receptors; the signaling source(s) is

unknown; (4) neuron-to-glia signaling; this involves A1, A2 and several P2Y receptor subtypes; the probable source of agonists are ganglion and amacrine cells; (5) autocrine

signaling in Mu ller glial cells (e.g. for volume regulation); this involves P2Y1 and A1 receptors; (6) glia-to-glia signaling (e.g. Ca2+ waves) of astrocytes and Mu ller cells; this

involves P2Y receptors; (60) signaling (e.g. Ca2+ waves) between RPE cells; (7) glia-to-neuron signaling, arising from Mu ller cells; this involves A1 receptors and not yet

specified P2X receptors; (8) glia-to-blood vessel signaling (control of blood flow), arising from astrocytes and Mu ller cells; (9) control of RPE functions including water

clearance from subretinal space; this involves P2Y2 receptors; the agonist source(s) is unknown; and (10) control of progenitor and Mu ller cell proliferation; this involves

several types of P2Y receptors (and, in culture, P2X7 receptors); the agonist source(s) is unknown. Abbreviations: A, amacrine cells; AS, astrocyte; B, bipolar cells; BV, blood

vessel; C, cone photoreceptor cell; G, retinal ganglion cells; GCL, ganglion cell layer; H, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer; M, Mu ller cell;

OFF, sublayer of the IPL where light-off information is processed; ON, sublayer of the IPL where light-on information is processed; ONL, outer nuclear layer; OPL, outer

plexiform layer; PRS, photoreceptors segments; R, rod photoreceptor cell; RPE, retinal pigment epithelium.


130


4/14

Adenosine suppresses excitatory neurotransmission in

the retina by various mechanisms (Table 1) including

inhibition of presynaptic voltage-dependent calcium chan-

nels resulting in reduced transmitter release, for example

of glutamate [2123], acetylcholine [4,18,24,25] and ATP

[4]. Adenosine inhibits the activity of N-methyl-D-aspar-

tate (NMDA) receptors [23,26] and phospholipase C [25],

and increases the activity of GABAAreceptor channels [27]

and KATP (ATP-sensitive K+) channels [28].

Neuronglia signaling and supportive functions

Purinergic signaling might be implicated in the bidirec-

tional dialogue between neurons and glial cells in the

retina. Flickering light was shown to increase the fre-

quency of Ca2+ transients in glial cells, which is likely to

be mediated by ATP released from neurons and sub-

sequent activation of P2Y receptors [20]. The purinergic

neuron-to-glia signaling might trigger an activation of glial

cells implicated in the light-evoked dilation and constric-

tion of retinal arterioles (neurovascular coupling) [29].

Adenosine increases the retinal blood flow through relaxa-

tion of pericytes [30]; a contribution of glia-derived adeno-sine, released in response to glutamate [8,31], remains to

be confirmed.

Purines released from retinal glial cells were suggested

to modulate synaptic activity [9]. Activation of glial cells,

for example by glutamate or electrical and mechanical

stimulation, triggers intercellular Ca2+ waves in the glial

network [32,33]. The propagation of the waves depends

upon the release of ATP and activation of P2Y receptors

[5,32] and is associated with an alteration in the light-

evoked activity of ganglion cells [33]. ATP released from

activated glial cells into the inner plexiform layer [5,9]

might be converted extracellularly to adenosine that acti-

vates A1 receptors in a population of ganglion cells, result-

ing in a depression of spontaneous activity [9,10].

Purines also regulate supportive functions of retinal glial

and pigment epithelial cells. Glutamatergic neurotrans-

mission in the retina is associated with changes in cellular

and extracellular volume [31,34] and with a decrease in the

osmolarity of the extracellular fluid [35]. Retinal glial cells

possess a purinergic signaling mechanism that maintains

their volume constant, to prevent a detrimentalshrinkage of

the extracellular space under hypo-osmotic conditions [34].

This mechanism involves the release of ATP and adenosine

and the autocrine activation of P2Y1 and A1 receptors [8,31]

and can be triggered by glutamate derived from neurons or

glial cells [31,34]. Activation of P2Y1, P2Y2 and A1 receptors

stimulates the absorption of excess fluid from the retinaltissue across the pigment epithelium [36,37] and, probably,

by glial cells [38]. This is required to redistribute metabo-

lically generated water (to prevent edema formation) and to

maintain a proper attachment of the neuroretina to the

pigment epithelium.

Retinal development

Purinergic signaling is involved in the early eye formation

and retinal development. In Xenopus laevis, ADP, extra-

cellularly formed from ATP, triggers the expression of the

eye field transcription factors Pax6 and Rx1, which are

necessary for eye development [39]. In the chick, ATP

stimulates the proliferation of early retinal progenitors

(by activation of P2Y2 and/or P2Y4 receptors) [7,40,41]

and of late glial and bipolar progenitors (by P2Y1 receptors)

[4244]. The division of progenitor cells in the ventricular

zone of the chick retina is likely to be stimulated by ATP

released from the pigment epithelium [7,45].

Retinal pathophysiology

Cellular proliferation is a common response of retinal glialcells to pathogenic stimuli involved in the formation of glial

scars [46]. Glial cell proliferation is stimulated by ATP

[47,48]; a bidirectional interaction between P2Y and

growth factor receptors seems to be involved in this effect.

The mitogenic effect of ATP depends on a release of growth

factors and on transactivation of growth factor receptor

tyrosine kinases [49], whereas growth factors trigger a

rapid resensitization of P2Y receptors, which are desensi-

tized by ATP [50]. However, the involvement of these

mechanisms in retina injuries in situ remains to be deter-

mined. Retinal gliosis in situ is characterized by an early

increase in P2-receptor-mediated Ca2+ responses

[47,51,52] indicating that ATP is one signal that initiatesretina protection and repair.

Excess ATP, released in response to pathogenic factors

such as mechanical perturbations [5,9] and elevated intra-

ocular pressure [5355], might be also implicated in

neuronal degeneration. P2X receptors are highly Ca2+

permeable [56]. Prolonged activation of P2X7 receptors

induces retinal ganglion cell death via Ca2+-dependent

mechanisms [57]. ATP-evoked ganglion cell death could

be involved in glaucoma [53]. The balance between extra-

cellular ATP and adenosine levels might determine the

level of ganglion cell death because adenosine inhibits the

P2X7-receptor-mediated Ca2+ rise and apoptosis of

ganglion cells [58]. However, whether ATP would be

released in levels high enough to overcome rapid conver-

sion to adenosine is not known. A rapid release of adeno-

sine is an important component of the retinal response to

ischemia or hypoxia [11,59]. Adenosine induces retinal

hyperemia after ischemia [60] and might protect neurons

from glutamate toxicity by suppression of excitatory neuro-

transmission. Activation of A1 and/or A2 receptors, or

ischemic preconditioning mediated by endogenous adeno-

sine and A1 receptor activation, protects the retina from

ischemic injury [28,61,62].

Olfaction

The nose of vertebrates utilizes various systems for che-

mosensation including the main olfactory system, vomer-onasal organ, Gruneberg ganglion and trigeminal system.

The main olfactory epithelium consists of olfactory recep-

tor neurons, glia-like sustentacular cells, microvillar cells

and basal cells. Here, extracellular ATP might be released

from receptor neurons and their axons [63,64], from sym-

pathetic and trigeminal nerve fibers [6567] and from cells

that are acutely injured by toxic compounds, for example

highly concentrated odorants [68]. It has been suggested

that there is a constant low level of extracellular ATP in the

main olfactory epithelium that induces a tonic suppression

of the activity of receptor neurons [69] and trigeminal

fibers [63].


131


5/14

In the main olfactory epithelium, ATP could activate

multiple P2 receptor subtypes expressed by receptor

neurons, sustentacular cells, basal cells (Figure 2;

Table 2), solitary microvillar cells [70] and trigeminal

nerve fibers. Activation of P2X and P2Y receptors in mur-

ine olfactory receptor neurons evokes inward currents and

cytosolic Ca2+ responses and reduces the odorant-induced

activity of the cells [69]; this indicates that P2 receptors

modulate odor sensitivity implicated, for example, in odor

adaptation. P1 and P2 receptors might also be involved in

olfactory receptor trafficking [71]. In sustentacular cells,

ATP evokes Ca2+ responses [69,72] and the opening of gap

junctions, thus enhancing the functional coupling between

the cells [73]. ATP released from injured cells could initiate

protective responses such as (i) reduction of the odorant

sensitivity of receptor neurons [69], (ii) induction of heat-

shock proteins in sustentacular cells, which might facili-

tate inhalant detoxification [68] and (iii) stimulation of

basal cell proliferation to regenerate the damaged tissue

[69]. Chemosensory trigeminal neurons express P2X2receptors; the suppression of P2X2 receptor currents by

distinct odorants might contribute to central odor recog-

nition [63]. In the vomeronasal organ, primary olfactory

neurons and secretory cells express purinergic receptors

[74].

Taste

Multiple purinergic signaling pathways contribute to the

coding and transmission of taste sensation, particularly for

taste buds, which occur on the tongue (lingual), palate and

larynx [75] (Figure 3; Table 3). In the taste bud, ATP is

released as a neurotransmitter and as a paracrine signal

for coupling taste cells with differing transduction modal-ities and gliasensory-cell communication. This occurs via

a non-vesicular mechanism involving pannexin 1 [76] and

connexin [77] hemichannels. Chemosensory cells and

fibers in the oral cavity and upper alimentary tract also

contribute to taste and broader chemosensory transduc-

tion, but with limited modality and less compelling evi-

dence for purinergic signaling.

ATP release from taste-bud type II receptor cells (TR-

expressing cells) is central to the coding of sweet, bitter and

umami taste, acting directly on P2X2 and P2X3 hetero-

meric receptors at the chemosensory afferent terminals

[75] of the chorda tympani branch of the facial nerve (n.

VII) and in the posterior aspect of tongue via glossophar-

yngeal (n. IX) innervation. The sweet modality utilizes the

T1R2T1R3 receptor dimer, with bitter tastes transduced

via a large family of T2R receptors and umani (the meati-

ness of monosodium glutamate) attributed to an N-term-

inal variant of the metabotropic glutamate mGlu4 receptor

and the T1R1T1R3 receptor dimer; these are all G-protein

coupled (for review, see Ref. [78]). In a P2X2/P2X3 double

knockout mouse model, all gustatory transmission was lost

from lingual taste buds [75]. Although the type II taste-bud

TR-expressing cells do not possess synaptic proteins,

recent transgenic mouse studies using T1R3 promoter/

enhancer-driven wheat germ aglutinin expression con-

firmed the intimate coupling of the sweet and umami type

Figure 2. Purinergic signaling in the olfactory epithelium. The following purinergic

paths are symbolized by the arrows: (1 and 10) modulation of signal integration

and/or firing rate; this involves several types of P2X and P2Y2 receptors; the

agonist source(s) might be other ORNs and/or efferent nerves; a possible

purinergic glia-to-neuron signaling remains to be determined; (2) neuron-to-glia

signaling might involve several types of P2X and P2Y1 and P2Y2 receptors; the

agonist source(s) is probably ORNs; (3) glia-to-glia signaling among the

sustentacular cells (Ca2+-wave-induced modification of gap-junctional coupling);

and (4) control of progenitor cell proliferation; this involves P2X1 and P2Y2receptors; the agonist source(s) might be ORNs and/or SCs. Abbreviations: BC,

basal cell; DK, dendritic knob; ORN, olfactory receptor neuron; SC, sustentacular

cell; TB, tubular bone.

Table 2. Expression of purinergic receptor subtypes in the main olfactory epitheliuma


Olfactory receptor neurons

P2X1, P2X4, P2Y2 Mouseb,d Elicitation of inward currents and Ca2+ responses; reduction in odor sensitivity [69]

P2X3, P2X5, P2X7 Ratd Not determined [74]

Sustentacular supporting cells

P2X5, P2X7, P2Y1 Ratd Not determined [74]

P2Y Mouseb,c Elicitation of Ca2+ responses; activation of BK channels; opening of gap junctions [69,73]

P2Y2, P2Y4 Moused, Xenopusb Elicitation of Ca2+ responses [69,72]

Basal cells

P2X1, P2Y2 Moused Not determined [69]

P2X7 Ratd Not determined [74]

aAbbreviations: BK, Ca2+-activated K+ channels of large conductance.

Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dimmunohistochemistry.


132


6/14

II receptor cells to the P2X-receptor-expressing intragem-

mal nerve fibers of the taste buds [79,80]; this is indicative

of direct purinergic transmission, albeit with unconven-

tional synaptic connectivity.

P2Y receptors probably modulate ATP (transmitter)

release via autocrine and paracrine feedback via the phos-

pholipase C (PLC)b2Ins(1,4,5)P3 [inositol (1,4,5)-trispho-

sphate]-receptor-3-gated Ca2+-store pathway. Several G-

protein heterotrimers are implicated in taste transduction

and add breadth to the response characteristics, whereas

transduction of the other two modalities (i.e. sour and

salty) involves additional transduction pathways [78].

The most notable markers of the taste-bud receptor cells

are the T1Rs, T2Rs, the bitter tastant G protein a gustdu-

cin, sweet tastant Ga14 [81], PLCb2 and the Ca2+-gatedtransient receptor potential channel TRPM5. The Ca2+

signal for triggering ATP release is likely to include the

TRPM5 channel and voltage-gated Na+ channels [77];

concurrent elevation of cytosolic Ca2+ and membrane

depolarization activate Px1 [82]. Encoding of tastant

responses might reflect the generator potential activity

of the receptor cells. Although receptor cells do not express

G-protein-coupled receptors for different tastant modal-

ities, there will be multi-modal integration of the tastant

responses at the chemoreceptor afferents because the same

fiber innervates multiple receptor cells [78] and the TR-

expressing cells and type III (presynaptic) taste cells are

coupled via P2X- and P2Y-receptor-mediated paracrinesignaling.

In addition to the direct coupling of the taste-bud TR-

expressing (type II) cells to a subset of purinergic intragem-

mal fibers, paracrine ATP signaling to the adjacent presyn-

aptic cells is likely to modulate the serotonergic

transmission at these conventional synapses via activation

of P2X and P2Y receptors. Ca2+ entry and release of Ca2+

from Ins(1,4,5)P3-gated stores provides a stimulus that

drives exocytosis of serotonin-containing synaptic vesicles

[76,78]. Serotonin might then activate chemoreceptor affer-

ents (as yet unconfirmed), and additional local release of

serotonin might itself have paracrine action within the taste

bud via serotonin 5-HT1 receptors [78,83]. The presynaptic

cells directly transduce tastants. For example, each taste

bud contains several of these cells that express the putative

sour-sensing TRP channel PKD2L1 [84]. Analysis of P2X

and P2Y expression highlights the functional coupling be-

tween all types of taste receptor cells. Given that each

mammalian taste bud contains $80 cells, ATP will diffuse

to adjacent receptor, synaptic and glial (type I) cells, in

addition to the precursor (type IV) cells, activating the full

range of these purinergic receptors, depending upon agonist

type (e.g. ATP versus ADP) and concentration.

It is notable that functional P2X7 receptor expression

has been identified in the mouse fungiform taste-bud cells,

implicating this pathway in the apoptotic mechanisms

associated with their rapid turnover [85]. These are prob-

Figure 3. Schematic summary of purinergic signalingin thetastebud.The following

purinergic paths are symbolized by the arrows: ATP is released from the (type II)

taste-bud receptor cells viapannexin1 (and connexin)hemichannels and(1) actsas a

neurotransmitter directly on the nerve endings of purinergic chemosensory afferent

fibers (via P2X2 and P2X3 receptors) to encode sweet, bitter and umami tastants; (2)

released ATP also has an autocrine and paracrine action on the receptor cells andprovides a coupling signal to the presynaptic (type III) taste-bud cells that release

serotonin as a neurotransmitter and neuromodulator (these are predominantly sour-

sensing cells);this is mediated by activation of P2X2 and P2Y1 receptorsto produce a

Ca2+ signal; (3) ATP autocrine action via P2Y1, P2Y2 and P2Y4 receptors to regulate

ATP release; (4) the enshrouding glial (type I) cells signal to the type IV cells, which

stimulate these precursor cells to sustain the replacement of the high turnover of

taste receptor cells; and (5) high levels of NTPDase2 on the cell surface of the type I

cells terminate the ATP signal.

Table 3. Expression of purinergic signaling elements in taste


Chorda tympani branch of VII glossopharyngeal n. IX superior laryngeal n. X taste-bud innervation

P2X1, P2X2, P2X3 Rate Chemosensory (taste) afferent [179,180]

P2X2P2X3 heteromer Mousee,g Chemosensory (taste) afferent [75]

Bud cells

Fungiform, circumvallate and foliate papillae

P2X2, P2X7 Mousea,b,c,e,f P2X2 on presynaptic cells fungiform papilla; P2X7 cell subtype not specified [85]

P2Y1 Rata,d,e,f Expressed in a subset of taste receptor and presynaptic cells; Ca 2+ increase with ATP [181]

P2Y1, P2Y2, P2Y4, P2Y6 Mousee,f Four dominant P2Y receptors; equally co-expressed in $75% of circumvallate and foliate

papillae taste-bud cells; Ca2+ responses

[85,182]

Expression of purinergic receptors was identified by the following methods: aCa2+ imaging; belectrophysiology; cpharmacology; din-situhybridization; eimmunohistochem-

istry; fRT-PCR; greceptor knockout.


133


7/14

ably presynaptic cells based on negative results (no change

in current) of theP2X7-selective agonist BzATP withvoltage

clamp of receptor cells from circumvallate taste buds [77].

ATP signaling within the lingual, palatal and laryngeal

taste buds is terminated by an ATP-selective ecto-nucleoti-

dase. An initial histochemical characterization of Ca2+-de-

pendent ecto-ATPase activity in taste buds from the golden

hamster showed strong labeling of the glial cells that

ensheath the receptor and presynaptic cells [86]. Genetranscript screening of taste-bud-enriched tissue, enzyme

activity assays and immunocytochemistry in mouse sub-

sequently identified this principally as nucleoside tripho-

sphate diphosphohydrolase-2 (NTPDase2), which is highly

selective for ATP over ADP [87]. Thus, ATP signaling is

tightly constrainedwithin thetastebud andunlikely to spill

overto activate purinergic sensory fibers for touch, tempera-

ture and pain [88].

Hearing

The cochlea exhibits a diverse array of purinergic signaling

components. This includes all sevenionotropic P2X receptor

subunits and all studied metabotropic P2Y receptors, inaddition to P1 receptor signaling via adenosine arising, in

part, from conversion of nucleotides by ecto-nucleotidases.

Figure 4 and Table 4 highlight important purinergic sig-

naling mechanisms supporting the maintenance of sound

transduction and neurotransmission in the cochlea.

Purinergic modulation of auditory neurotransmission

A role for extracellular ATP as an effector of cochlear

neurotransmission was identified earlier than glutamate

[89]. Perfusion of the scala tympani (i.e. into the perilymph)

with P2X receptor agonists and antagonists suppresses and

enhances, respectively, the compound action potential

[90,91], supporting a role for regulation of primary afferent

neurite excitability [91]. In the adult rat and guinea-pig

spiral ganglion neurons, the predominant P2X receptors are

P2X2 andP2X7. Agonists of P2X2,butnotP2X7, have a direct

action on individual afferent auditory fibers affecting the

breadth of the tuning curve [92]. P2X2 has been localized to

the postsynaptic specializations at the spiral ganglionneuron neuritehair-cell synapses at both inner and outer

hair cells [93], and both type I and type II spiral ganglion

neurons exhibit ATP-gatedinward currents at thecell soma

[94]. Glucocorticoids enhance the P2X receptor signaling

and elicit nitric oxideproduction by the cells, which provides

local signaling[95], potentially interacting withthe satellite

glial cells. P2Y receptor activation in the soma of the spiral

ganglionneurons elicits Ca2+ signaling[96], which recruits a

substantial nonselective cation conductance, impacting on

primary afferent excitability [97]. The outer hair cells are

also innervated by cholinergic (olivocochlear) efferent fibers

that act to reduce hearing sensitivity by modulating outer

hair cell-mediated reverse transduction. P2X7 receptorexpression occurs presynaptically[98] and might influence

this neural feedback.

Paracrine signaling supports cochlear homeostasis

In the rodent cochlea, both P2X and P2Y receptors are

extensively expressed in the cochlear partition, and via

autocrine and paracrine action they are likely to reduce the

driving force forsound transduction when stressors such as

acoustic overstimulation or ischemia cause the release of

ATP into the scala media. P2X2 receptors, in particular, are

Figure 4. Schematic summary of purinergic signaling in the cochlea. The following purinergic paths are symbolized by the arrows: (1) ATP in marginal cells is contained in

vesicles and provides autocrine and paracrine action to inhibit K+ influx into the scala media by a P2Y4 receptorPLC PKC pathway closing KCNE1/KCNQ1 K+ channels; this

acts in synergy with pathway (5); (2) internal K+-transport regulation within the stria vascularis; this is via the P2Y4 receptor; (3) strial blood vessels; A2A-receptor-mediated

vasodilatation with ischemia; (4) regulation of K+ recycling between perilymph and endolymph via Ca2+ signaling and connexins in the spiral limbus and spiral ligament;

this is via A1, P2X2 and P2Y receptors; (5) K+ shunt out of the endolymph via ATP-gated nonselective channels (which decreases the EP and depolarizes hair cells) works in

synergy with pathway (1); this is mediated by the P2X2 receptor; (6) autocrine action: multiple signaling pathways within the hair cells and adjacent supporting cells affect

the membrane potential and micromechanics of the hair cells and supporting cells, Ca 2+ and nitric oxide signaling; this is via P2X2 and P2X7, and P2Y2 and P2Y4 receptors;

(7) paracellular epithelial ion homeostasis in inner and outer sulcus (connexin and pannexin 1 hemichannels); Ca2+ waves and K+ re-absorption during acoustic

overstimulation; this is via P2X2 and P2Y4 receptors; (8) postsynaptic actions at the afferent (spiral ganglion) neurites and terminals at the hair cells (neuromodulation);

during synaptic consolidation before hearing onset, activity to inhibit neurite extension by blocking Trk signaling of neurotrophins; this is via P2X2 and P2X2/P2X3 receptors;

(9) spiral ganglion neuronneuron or satellite cell (glia)-to-neuron signaling; Ca2+ signaling activates BK channels, regulating spontaneous activity; via A1, A2A and A3, P2X2and P2X7 receptors (P2X1 and P2X3 during development) and the P2Y receptor; and (10) efferent fiberhair cell presynaptic regulation of cholinergic efferent inhibition of

outer hair-cell electromotility; this is via the P2X7 receptor. Abbreviations: BM, basilar membrane; BV, blood vessel; DC, Deiters cell; HC, Hensens cell; IDC, interdental cells;

IHC, inner hair cell; IS, inner sulcus; ISP, inner spiral plexus; OHC, outer hair cell; RM, Reissners membrane; SGN, spiral ganglion neuron; ScM, scala media; ScT, scala

tympani; ScV, scala vestibuli; SLG, spiral ligament; SP, spiral prominence; SV, stria vascularis; TM, tectorial membrane.


134


8/14

highly expressed on the apical surfaces of the cells facing

the endolymphatic compartment. This includes Reissners

membrane (a two-cell-thick resistive barrier between the

scala media and scala vestibuli), in addition to the inner

and outer sulcus regions and hair cells of the organ of Corti

[93,99,100]. All these cells have tight junctions that main-

tain the integrity of the endolymphatic compartment. The

adjacent stria vascularis has a K+ transporter system that

generates the endocochlear potential (EP;$+100 mV). The

EP provides the majority of the driving force for sound

transduction [101]. Physiological experiments and bio-

chemical analysis has shown that the ionotropic and meta-

botropic signaling pathways act in synergy to regulate

electrochemical homeostasis. ATP released into this com-

Table 4. Expression of purinergic signaling elements in the cochleaa


Reissners membrane

Epithelial cells

P2X1, P2X2 Rate,f Transient downregulated by P10 [183]

P2X2 Rate K+ shunt from endolymph, protection against acoustic overstimulation [184]

P2X2 Guinea-pigc,f,h K+ shunt from endolymph, protection against acoustic overstimulation [185]

P2X2 Mousei K+ shunt from endolymph, protection against acoustic overstimulation Housley, G.D.

et al. (abstract)j

Stria vascularis: marginal, intermediate and basal cells

P2Y2, P2Y4 Gerbil, ratc,f P2Y4 on apical surface inhibits KCNE1/KCNQ1 K

+ channel via PKC; protection

against acoustic overstimulation

[108,186]

Endothelial cells of the strial blood vessels

A2A, A3 Ratf Vasodilatation [135]

Spiral ligament (fibrocytes)

A2A, A3 Ratf Ion recycling [135]

P2X2 Rate,f Ion recycling [100,184]

Outer sulcus epithelial cells (Bottchers and Claudius cells)

P2X2 Rate,f Paracellular ion recycling [100,184]

P2X2 Mousef Ion homeostasis [187]

P2X2 Gerbilc Activates nonselective cation channels to shunt K+ from endolymph [188]

P2Y4 Ratc Ion homeostasis [189]

Organ of Corti

Inner and outer hair cells

P2X2 Guinea-pigc,f,g Functionally localized to the apical surface; protection against acoustic

overstimulation

[93,110,112]

P2X2 Rate,f K+ shunt, cell deploarization and micromechanics [99,100,113,184]

P2X2 Mousef K+ shunt, cell deploarization and micromechanics [187]

P2X7 Ratf Function unknown [98]

P2Y1, P2Y2, P2Y4 Guinea-pigb,c,f PLC; Ins(1,4,5)P3; Ca

2+ signaling affects transduction [114,115]

A1, A2A, A3 Ratf Anti-oxidant stress response [135]

Supporting cells (Deiters cell, Hensens cells, pillar cells, inner phalangeal cells)

A1, A2A, A3 Ratf Otoprotective against ROS [135]

P2 Guinea-pigc Regulates micromechanics [118]

P2X2 Rate,f Micromechanics [100,184]

P2X2 Mousef Micromechanics [187]

P2X7 Ratf Micromechanics [98]

P2Y Rat PLC; Ins(1,4,5)P3; injury signal through JNK; ERK1/2 signaling

P2Y4 Guinea-pigf Might indicate paracrine ATP release and Ca2+ signaling [190]

Inner sulcus

P2X2 Rate,f Affects K+ shunt and ion homeostasis [100,184]

Interdental cells of the spiral limbusP2X2 Rat

e,f Possible role in ion homeostasis [100,184]

Spiral limbus fibrocytes

P2X1 Rate,f Transient down-regulated by P10 [183]

P2X2 Rate,f Ion homeostasis [100,184]

Spiral ganglion neurons

A1, A2A, A3 Ratf Protection from ROS [135]

P2X1, P2X2, P2X3, P2X4,

P2X5, P2X6, P2X7

Ratc,d,f,h P2X2 and P2X7 sustained; P2X2/P2X3 early postnatal [98,99,122,125,

183,191193]

P2Y Guinea-pigd PLC; Ins(1,4,5)P3 [96,192]

P2Y Ratc Regulates neuron excitability [97]

Olivocochlear efferent fibers (bundle)

P2X1 Rate,f Transient downregulation by P10 [183]

P2X7 Ratf Presynaptic; regulates ACh release [98]

Mesenchymal cells

P2X1 Rate,f Transiently expressed during development; downregulated by P10 [183]

aAbbreviations: Ach,acetylcholine;ERK, extracellular signal-regulated kinase;JNK, c-Jun N-terminal kinase; P10,postnatal day10; PKC,protein kinase C; PLC,phospholipaseC; ROS, reactive oxygen species.

Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dradioligand labeling; ein-situhybridization; fimmunohis-

tochemistry; gelectron microscopy; hRTPCR; ireceptor knockout.jHousley, G.D. et al. (2008) ATP-mediated humoral inhibition ofsound transduction supplants neural efferent inhibitionat high sound levels as the mechanismfor expanding

the dynamic range of hearing [abstract]. Assoc. Res. Otolaryngol. Abstract 623 (www.aro.org/archives/2008/2008_623_bf2a42ab.html ).


135
http://www.aro.org/archives/2008/2008_623_bf2a42ab.htmlhttp://www.aro.org/archives/2008/2008_623_bf2a42ab.html


9/14

partment during the stress of noise or hypoxia, including

release from vesiculated stores in the stria vascularis

[102,103] and release from the organ of Corti [104], would

activate the P2X2 receptors and produce a shunt conduc-

tance. This shunt has been demonstrated as a reduction

in the cochlear partition resistance in the guinea-pig

when ATP is injected into the endolymph [105]. This

causes a reversible reduction in EP. The ATP signal is

terminated by ecto-nucleotidase activity [106]. Comple-menting this P2X-receptor-mediated shunt of K+ (and

other minor cations) out of the scala media, the electro-

chemical driving force for sound transduction is also

decreased by P2Y4 receptorPLCprotein kinase C

(PKC)-mediated inhibition of the KCNE1/KCNQ1 chan-

nels, which provide the K+-influx pathway from the stria

vascularis [107,108].

Outer hair cells have a keyrole in sound transduction via

their electromotility, a unique property that enhances hear-

ing sensitivity and frequency selectivity[109]. Extracellular

ATP acts at nanomolar levels [110] to affect the non-linear

capacitance of the electromotility via P2Y receptor sig-

naling. At micromolar ATP levels, P2X2-receptor-gatedinward current would alter the electromotility by depolar-

izing the cells and by osmotically induced changes in cell

volume [111]. The hair-cell P2X-receptor-mediated shunt is

adaptive to noise stress. Very high densities of P2X2 recep-

tors are present on the stereocilia and cuticular plates of the

hair cells, but not the basolateral surface [93,112]. Intherat

model, after 72 h of 90 dB broadband noise, the ATP-gated

inward current in outer hair cells increased more than

threefold, which correlated with enhanced P2X2 immuno-

labelling on the stereocilia [113]. There was also an upre-

gulation in P2X2 transcript expression in the surrounding

cochlear partition epithelium, detected at 6 hours of sus-

tained noise exposure onwards.

Sound transduction in outer hair cells might also be

affected by P2Y-receptor-mediated Ca2+ signaling. P2Y2immunolabeling localizes to the apical region of the

guinea-pig outer hair cells [114]. Hensens body, an

Ins(1,4,5)P3-receptor-gated Ca2+ store under the cuticular

plate, is activated by this P2Y receptor signaling via liber-

ation of a G protein in the hair bundle, and the localized

elevation in Ca2+ probably alters actin binding, affecting

stereocilia stiffness [115]. P2-receptor-mediated Ca2+ sig-

naling within Deiters cells, originating in the apical pha-

langeal processthat projects to the reticular lamina between

the outer hair-cell cuticular plates, causes changes in the

stiffness of the cells that would affect transduction [116

118].Overall, purinergic signaling in the cochlear partition

can be viewed as a protective adaptation mechanism. As

the sound level rises, elevation of ATP from a low nano-

molar concentration [103,119] would activate the puriner-

gic signaling pathways, desensitize the transduction and

transmission processes and thereby extend the safe range

for hearing from the level where the neural efferent inhi-

bition of the outer hair cells saturates [120].

Cochlear development

During development, both type I and type II spiral

ganglion neurons undertake promiscuous innervation of

inner and outer hair cells. This is followed by programmed

pruning of mis-matched fibers, with the type I spiral

ganglion neurons withdrawing from the outer hair cells

and the type II fibers withdrawing from the inner hair

cells. This neural re-organization occurs within a few days

after birth in rodents, just before the onset of hearing. The

outgrowth and branching of the spiral ganglion neurites is

supported by neurotrophins secreted by the hair cells,

particularly brain-derived neurotrophic factor (BDNF)and neurotrophin 3 via TrkB and TrkC receptor tyrosine

kinase signaling, respectively [121]. P2X receptor sig-

naling contributes to the uncoupling of this neurotrophic

support. This is mediated by the transient expression of a

novel P2X2P2X3 heteromeric receptor, incorporating an

uncommon (P2X2-3) splice variant [122125] that exhibits

nanomolar ATP sensitivity. Activation of this receptor

blocks the BDNF-dependent outgrowth of the neurites

[125].

Extracellular nucleotide signaling also underlies the

induction of neurotransmission in the newly established

innervation of the inner hair cells. Paracrine ATP sig-

naling is central to this process. The neonatal cochlea isstructurally distinct in having a transient epithelium (the

Kollikers organ) medial to the inner hair cells. The Kolli-

kers organ epithelial cells spontaneously secrete ATP in

rhythmical bursts that activate P2 receptors on the inner

hair cells [126]. This, in turn, elicits synchronized release of

neurotransmitter from the inner hair cells, which activates

the type I spiral ganglion neurons. The effect involves ATP-

induced ATP release and can be blocked by treating the

tissue with apyrase, which hydrolyses endogenous ATP.

The purinergic receptors involved in this process, and the

pathway for release of ATP, have not been characterized at

a molecular level but involve both P2X and P2Y receptors

causing ATP release via connexin hemichannels in Kolli-

kers organ. ATP diffuses to the inner hair cells, where

inward currents, consistent with activation of P2X recep-

tors, lead to Ca2+ influx and pulsatile release of glutamate

at the ribbon synapses with the spiral ganglion neurites.

Rhythmic firing in the cochlear nerve ceases around the

time that the auditory canal opens in rodents ($P11), and

sound-conduction-induced activity commences. This ATP-

mediated activation of cochlear primary-afferent firing is

associated with the maturation of the central auditory

pathways, particularly the cochlear nuclei, and probably

consolidates the central synaptic mapping of cochlear

tonotopy [127].

Cochlear pathophysiologyATP release in the supporting cells of the organ of Corti

and spiral ligament is mediated via connexin [110] and

probably also pannexin 1 hemichannels [128]. Gap junc-

tions, particularly heteromers of Cx26 and Cx30, form the

conduit for ionic recirculation between the perilymph and

endolymph in response to the standing flux through the

hair cells [129,130]. Disruption of this conduit leads to

pathological changes in structure and function, which

might arise, in part, from theblock of purinergic signaling.

Ca2+ signaling between gap-junction-coupled cells

involves Cx and Px hemichannel-mediated ATP release,

which, with positive feedback, actsupon P2Y2 and/or P2Y4


136


10/14

receptors to promote further Ins(1,4,5)P3 production via

the GqPLCbIns(1,4,5)P3 pathway and Ca2+ release

[131]. Rapid propagation of the Ca2+ signal occurs as

ATP diffuses to adjacent cells. The propagation of Ca2+

waves can be blocked by apyrase [132], as shown for the

ATP release in Kollikers organ during development [126].

This extracellular ATP-dependent Ca2+-signaling mech-

anism can be invoked by thedeath of a singlehaircell [132]

and might reflect a cochlear tissue-injury response. Theoscillatory Ca2+ waves in the organ of Corti supporting

cells and outer sulcus evoke a variety of spatiotemporal

injury responses in the tissue, including activating mem-

bers of the mitogen-activated protein kinase pathway,

including c-Jun N-terminal kinase (JNK) activity and

extracellularly regulated kinases 1 and 2 (ERK1/2)

[132,133], leading to hair-cell encroachment and scarring

of the reticular lamina.

Adenosine is otoprotective. In the cochlea, it can be

released from cells by bidirectional equilibrative and con-

centrative adenosine transporters [134] and by sequential

nucleotide hydrolysis via ectoNTPDases and 5-ecto-nucleo-

tidase activity, to be available to activate the four adeno-sine receptor subtypes [135]. In an acoustic

overstimulation model in gerbils, A1 receptor upregulation

was induced by reactive oxygen species (ROS) and nuclear

factor kB signaling[136]. Adenosine A1 receptor agonists

increase cochlear glutathione peroxidase and superoxide

dismutase expression that confers protection against ROS-

mediated ototoxicity arising from platinum-based che-

motherapy agents [137139].

Conclusions

Summarizing the data, there is considerable commonal-

ity among the different senses. In all cases, stimulus

transduction and information processing are modulated

by purinergic signaling. Moreover, the crosstalk between

neurons and supporting cells such as glial cells, retinal

pigment epithelial cells and sustentacular cells, in

addition to the signaling between the supporting cells,

involves purinergic pathways. Finally, the control of

progenitor proliferation and other developmental events,

in addition to the regulation of basal and glial cell

proliferation to protect and regenerate the damaged

tissues, seem to involve purinergic signaling. These sim-

ilarities are often reflected in particular subtypes of

purinergic receptors. For instance, P2Y1 and P2Y2 recep-

tors are characteristic for pathways to and among sup-

porting and glial cells, whereas P2X2 (or P2X2/3) and

P2X7 receptors frequently occur on sensory neurons.Currently, little is known about P1 adenosine receptors

in smell and taste, but, within the retina and inner ear,

A1 and A2 receptor action complements P2 signaling in

homeostatic roles. Usually, however, the previously men-

tioned rules of purinergic signaling are characteristic

not only for the sensory organs but also for other parts of

the central and peripheral nervous systems [2]. Thus, the

present state of our knowledge supports the conclusion

that purinergic signaling in a given part of the nervous

system is neither primarily determined by its ontogenetic

origin (i.e. from neural plate versus neural crest) nor by

any adaptation to specific tasks in information processing

(e.g. to different adequate stimuli). Rather, the puriner-

gic system seems to be a phylogenetically old and rather

universally usable and versatile tool to control the de-

velopment and diverse cellular interactions of the

vertebrate nervous system and fine-tune information

processing within it.

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (RE8 4 9 /1 2 ; G RK 1 0 9 7/1 ; www.dfg.de/en) g ra nt s t o A .R ., b y t h e

Bundesministerium fur Bildung und Forschung (DLR/01GZ0703;

www.bmbf.de) grant to A.R., by the Interdisziplinares Zentrum fur

Klinische Forschung (www.izkf-leipzig.de) at the Faculty of Medicine of

the University of Leipzig (C35, Z10) grant to A.B., and by National

Health and Medical Research Council, Australia (www.nhmrc.gov.au),

Health Research Council, New Zealand (www.hrc.govt.nz) and Marsden

Fund (Royal Society of New Zealand; www.marsden.rsnz.org) grants to

G . D. H . G r ap h ic c o nt r ib u ti o ns b y J e ns G r os c h e i s g r at e fu l ly

acknowledged.

References1 Burnstock, G. (2007) Physiology and pathophysiology of purinergic

neurotransmission. Physiol. Rev. 87, 659797

2 Abbracchio, M.P. et al. (2009) Purinergic signalling in the nervous

system: an overview. Trends Neurosci. 32, 19

293 Perez, M.T.R. et al. (1986) Release of endogenous and radioactive

purines from the rabbit retina. Brain Res. 398, 106112

4 Santos, P.F. et al. (1999) Characterization of ATP release from

cultures enriched in cholinergic amacrine-like neurons. J.

Neurobiol. 41, 340348

5 Newman, E.A. (2001) Propagation of intercellular calcium waves in

retinal astrocytes and Muller cells. J. Neurosci. 21, 22152223

6 Mitchell, C.H. (2001) Release of ATP by a human retinal pigment

epithelial cell line: potential for autocrine stimulation through

subretinal space. J. Physiol. 534, 193202

7 Pearson, R.A. et a l. (2005) ATP released via gap junction

hemichannels from the pigment epithelium regulates neural

retinal progenitor proliferation. Neuron 46, 731744

8 Uckermann, O. et al. (2006) Glutamate release by neurons evokes a

purinergic inhibitory mechanism of osmotic glial cell swelling in the

rat retina: activation by neuropeptide Y. J. Neurosci.Res. 83, 538

5509 Newman, E.A. (2003) Glial cell inhibition of neurons by release of

ATP. J. Neurosci. 23, 16591666

10 Newman, E.A. (2004)Glialmodulation ofsynaptic transmission in the

retina. Glia 47, 268274

11 Ribelayga, C. andMangel, S.C. (2005)A circadianclock andlight/dark

adaptation differentially regulate adenosine in mammalian retina. J.

Neurosci. 25, 215222

12 Puthussery, T.etal. (2006) Evidence forthe involvement of purinergic

P2X7 receptors in outer retinal processing. Eur. J. Neurosci. 24,

719

13 Puthussery, T. and Fletcher, E.L. (2007) Neuronal expression of P2X3purinoceptors in the rat retina. Neuroscience 146, 403414

14 Iandiev, I. et al. (2007) Ecto-nucleotidases in Muller glial cells of the

rodent retina: involvement in inhibition of osmotic cell swelling.

Purinergic Signal. 3, 423433

15 Puthussery, T. and Fletcher, E.L. (2006) P2X2 receptors on ganglionand amacrine cells in cone pathways of the rat retina. J. Comp.

Neurol. 496, 595609

16 Puthussery, T. and Fletcher, E.L. (2004) Synaptic localization of P2X7receptors in the rat retina. J. Comp. Neurol. 472, 1323

17 Kaneda, M. et al. (2008) Pathway-dependent modulation by

P2-purinoceptors in the mouse retina. Eur. J. Neurosci. 28, 128

136

18 Kaneda, M. et al. (2004) OFF-cholinergic-pathway-selective

localization of P2X2 purinoceptors in the mouse retina. J. Comp.

Neurol. 476, 103111

19 Neal, M. and Cunningham, J. (1994) Modulation by endogenous ATP

of the light-evoked release of ACh from retinal cholinergic neurones.

Br. J. Pharmacol. 113, 10851087

20 Newman, E.A. (2005) Calcium increases in retinal glial cells evoked

by light-induced neuronal activity. J. Neurosci. 25, 55025510


137
http://www.dfg.de/enhttp://www.bmbf.de/http://www.izkf-leipzig.de/http://www.hrc.govt.nz/http://www.marsden.rsnz.org/http://www.marsden.rsnz.org/http://www.hrc.govt.nz/http://www.izkf-leipzig.de/http://www.bmbf.de/http://www.dfg.de/en


11/14

21 Stella, S.L., Jr et al. (2003) Endogenous adenosine reduces

glutamatergic output from rods through activation of A2-like

adenosine receptors. J. Neurophysiol. 90, 165174

22 Sun, X. et al. (2002) Adenosine inhibits calcium channel currents via

A1 receptors on salamander retinal ganglion cells in a mini-slice

preparation. J. Neurochem. 81, 550556

23 Hartwick, A.T. et al. (2004) Adenosine A1-receptor modulation of

glutamate-induced calcium influx in rat retinal ganglion cells.

Invest. Ophthalmol. Vis. Sci. 45, 37403748

24 Blazynski, C. et al. (1992) Evidence for the action of endogenous

adenosine in the rabbit retina: modulation of the light-evokedrelease of acetylcholine. J. Neurochem. 58, 761767

25 Santos, P.F.etal. (2000) Adenosine A1 receptors inhibit Ca2+ channels

coupled to the release of ACh, but not of GABA, in cultured retina

cells. Brain Res. 852, 1015

26 Costenla, A.R. et al. (1999) An adenosine analogue inhibits NMDA

receptor-mediated responses in bipolar cells of the rat retina.Exp. Eye

Res. 68, 367370

27 Feigenspan, A. and Bormann, J. (1994) Facilitation of GABAergic

signaling in the retina by receptors stimulating adenylate cyclase.

Proc. Natl. Acad. Sci. U. S. A. 91, 1089310897

28 Sakamoto, K. et al. (2004) Histological protection against ischemia-

reperfusion injury by early ischemic preconditioning in rat retina.

Brain Res. 1015, 154160

29 Metea, M.R. and Newman, E.A. (2006) Glial cells dilate and constrict

bloodvessels: a mechanism of neurovascular coupling.J. Neurosci. 26,

2862

287030 Li, Q. and Puro, D.G. (2001) Adenosine activates ATP-sensitive K+

currents in pericytes of rat retinal microvessels: role of A1 and A2areceptors. Brain Res. 907, 9399

31 Wurm, A.etal. (2008) Glial cell-derived glutamate mediates autocrine

cell volume regulation in the retina: activation by VEGF. J.

Neurochem. 104, 386399

32 Newman, E.A. and Zahs, K.R. (1997) Calcium waves in retinal glial

cells. Science 275, 844847

33 Newman, E.A. and Zahs, K.R. (1998) Modulation of neuronal activity

by glial cells in the retina. J. Neurosci. 18, 40224028

34 Uckermann, O.et al. (2004) Glutamate-evoked alterations of glial and

neuronal cell morphology in the guinea-pig retina. J. Neurosci. 24,

1014910158

35 Dmitriev, A.V. et al. (1999) Light-induced changes of extracellular

ions and volume in the isolated chick retina-pigment epithelium

preparation. Vis. Neurosci. 16, 1157

116736 Maminishkis, A. et al. (2002) The P2Y2 receptor agonist INS37217

stimulates RPE fluid transport in vitro and retinal reattachment in

rat. Invest. Ophthalmol. Vis. Sci 43, 35553566

37 Meyer, C.H. et al. (2002) The effects of INS37217, a P2Y2receptor agonist, on experimental retinal detachment and

electroretinogram in adult rabbits. Invest. Ophthalmol. Vis. Sci. 43,

35673574

38 Reichenbach, A. et al. (2007) Muller cells as players in retinal

degeneration and edema. Graefes Arch. Clin. Exp. Ophthalmol. 245,

627636

39 Masse, K. et al. (2007) Purine-mediated signalling triggers eye

development. Nature 449, 10581062

40 Sugioka, M. et al. (1999) Involvement of P2 purinoceptors in the

regulation of DNA synthesis in the neural retina of chick embryo.

Int. J. Dev. Neurosci. 17, 135144

41 Pearson, R. et al. (2002) Purinergic and muscarinic modulation of thecell cycle and calcium signaling in the chick retinal ventricular zone.

J. Neurosci. 22, 75697579

42 Nunes, P.H.C. et al. (2007) Signal transduction pathways associated

with ATP-induced proliferation of cell progenitors in the intact

embryonic retina. Int. J. Dev. Neurosci. 25, 499508

43 Sanches, G. et al. (2002) ATP induces proliferation of retinal cells in

culture via activation of PKC and extracellular signal-regulated

kinase cascade. Int. J. Dev. Neurosci. 20, 2127

44 Franca, G.R. et al. (2007) ATP-induced proliferation of developing

retinal cells: regulation by factors released from postmitotic cells in

culture. Int. J. Dev. Neurosci. 25, 283291

45 Pearson, R.A. et al. (2004) Ca2+ signalling and gap junction coupling

within and between pigment epithelium and neural retina in the

developing chick. Eur. J. Neurosci. 19, 24352445

46 Bringmann, A. et al. (2006) Muller cells in the healthy and diseased

retina. Prog. Retin. Eye Res. 25, 397424

47 Bringmann, A.et al. (2001) Upregulation of P2X7 receptor currents in

Muller glial cells during proliferative vitreoretinopathy. Invest.

Ophthalmol. Vis. Sci. 42, 860867

48 Moll, V. et al. (2002) P2Y receptor-mediated stimulation of Muller

glial DNA synthesis. Invest. Ophthalmol. Vis. Sci. 43, 766773

49 Milenkovic, I. et al. (2003) P2Y receptor-mediated stimulation of

Muller glial cell DNA synthesis: dependence on EGF and PDGF

receptor transactivation. Invest. Ophthalmol. Vis. Sci. 44, 12111220

50 Weick, M. et al. (2005) Resensitization of P2Y receptors by growthfactor-mediated activation of the phosphatidylinositol-3 kinase in

retinal glial cells. Invest. Ophthalmol. Vis. Sci. 46, 15251532

51 Francke, M. et al. (2002) Up-regulation of extracellular ATP-induced

Muller cell responses in a dispase model of proliferative

vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 43, 870881

52 Uhlmann, S. et al. (2003) Early glial cell reactivity in experimental

retinal detachment:effect of suramin.Invest. Ophthalmol.Vis. Sci. 44,

41144122

53 Resta, V. et al. (2007) Acute retinal ganglion cell injury caused by

intraocular pressure spikes is mediated by endogenous extracellular

ATP. Eur. J. Neurosci. 25, 27412754

54 Reigada, D. et al. (2008) Elevated pressure triggers a physiological

release of ATP from the retina: possible role for pannexin

hemichannels. Neuroscience 157, 396404

55 Zhang, X. et al. (2007) Acute increase of intraocular pressure releases

ATP into the anterior chamber. Exp. Eye Res. 85, 637

64356 Evans, R.J. et al. (1996) Ionic permeability of, and divalent cation

effects on, two ATP-gated cation channels (P2X receptors) expressed

in mammalian cells. J. Physiol. 497, 413422

57 Zhang, X.etal. (2005) Stimulation of P2X7 receptors elevates Ca2+ and

kills retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 46, 2183

2191

58 Zhang, X.et al. (2006) Balance of purines may determine life or death

of retinal ganglion cells as A3 adenosine receptors prevent loss

following P2X7 receptor stimulation. J. Neurochem. 98, 566575

59 Roth, S. et al. (1997) Ischemia induces significant changes in purine

concentration in the retina-choroid in rats. Exp. Eye Res. 65, 771

779

60 Ostwald, P. et al. (1997) Adenosine receptor blockade and nitric oxide

synthase inhibition in the retina: impact upon post-ischemic

hyperemia and the electroretinogram. Vision Res. 37, 34533461

61 Larsen, A.K. and Osborne, N.N. (1996) Involvement of adenosine inretinal ischemia. Studies on the rat. Invest. Ophthalmol. Vis. Sci. 37,

26032611

62 Ghiardi, G.J. et al. (1999) The purine nucleoside adenosine in retinal

ischemia-reperfusion injury. Vision Res. 39, 25192535

63 Spehr, J. et al. (2004) Subunit-specific P2X-receptor expression

defines chemosensory properties of trigeminal neurons. Eur. J.

Neurosci. 19, 24972510

64 Rieger, A. et al. (2007) Axon-glia communication evokes calcium

signaling in olfactory ensheathing cells of the developing olfactory

bulb. Glia 55, 352359

65 Finger, T.E. et al. (1990) Ultrastructure of substance P- and CGRP-

immunoreactive nerve fibers in the nasal epithelium of rodents. J.

Comp. Neurol. 294, 293305

66 Getchell, M.L. and Getchell, T.V. (1992) Fine structural aspects of

secretion and extrinsic innervation in the olfactory mucosa. Microsc.

Res. Tech. 23, 111

12767 Liang, S.D. and Vizi, E.S. (1997) Positive feedback modulation of

acetylcholine release from isolated rat superior cervical ganglion.

J. Pharmacol. Exp. Ther. 280, 650655

68 Hegg, C.C. and Lucero, M.T. (2006) Purinergic receptor antagonists

inhibit odorant-induced heat shock protein 25 induction in mouse

olfactory epithelium. Glia 53, 182190

69 Hegg, C.C. et al. (2003) Activation of purinergic receptor subtypes

modulates odor sensitivity. J. Neurosci. 23, 82918301

70 Gulbransen, B.D. et al. (2008) Nasal solitary chemoreceptor cell

responses to bitter and trigeminal stimulants in vitro.

J. Neurophysiol. 99, 29292937

71 Bush, C.F. et al. (2007) Specificity of olfactory receptor interactions

with other G protein-coupled receptors. J. Biol. Chem. 282, 19042

19051


138


12/14

72 Hassenklover, T. et al. (2008) Nucleotide-induced Ca2+ signaling in

sustentacular supporting cells of the olfactory epithelium. Glia 56,

16141624

73 Vogalis, F.etal. (2005)Electrical coupling in sustentacularcells of the

mouse olfactory epithelium. J. Neurophysiol. 94, 10011012

74 Gayle, S. and Burnstock, G. (2005) Immunolocalisation of P2X and

P2Ynucleotidereceptors in therat nasal mucosa. Cell TissueRes. 319,

2736

75 Finger, T.E. et al. (2005) ATP signaling is crucial for communication

from taste buds to gustatory nerves. Science 310, 14951499

76 Huang, Y.J. et al. (2007) The role of pannexin 1 hemichannels in ATPrelease and cellcell communication in mouse taste buds. Proc. Natl.

Acad. Sci. U. S. A. 104, 64366441

77 Romanov, R.A. et al. (2007) Afferent neurotransmission mediated by

hemichannels in mammalian taste cells. EMBO J. 26, 657667

78 Roper, S.D. (2007) Signal transduction and information processing in

mammalian taste buds. Pflugers Arch. 454, 759776

79 Ohmoto, M. et al. (2008) Genetic tracing of the gustatory and

trigeminal neural pathways originating from T1R3-expressing

taste receptor cells and solitary chemoreceptor cells. Mol. Cell.

Neurosci. 38, 505517

80 Damak, S. et al. (2008) Transsynaptic transport of wheat germ

agglutinin expressed in a subset of type II taste cells of transgenic

mice. BMC Neurosci. 9, 96

81 Tizzano, M. et al. (2008) Expression of Ga14 in sweet-transducing

taste cells of the posterior tongue. BMC Neurosci. 9, 110

82 Bao, L. et al. (2004) Pannexin membrane channels aremechanosensitive conduits for ATP. FEBS Lett. 572, 6568

83 Huang, Y.J. et al. (2005) Mouse taste buds use serotonin as a

neurotransmitter. J. Neurosci. 25, 843847

84 Kataoka, S.et al. (2008) The candidate sour taste receptor, PKD2L1,is

expressed by typeIII taste cellsin themouse. Chem. Senses 33,243254

85 Hayato, R.et al. (2007) Functional expression of ionotropic purinergic

receptors on mouse taste bud cells. J. Physiol. 584, 473488

86 Barry, M.A. (1992) Ecto-calcium-dependent ATPase activity of

mammalian taste bud cells. J. Histochem. Cytochem. 40, 19191928

87 Bartel, D.L. et al. (2006) Nucleoside triphosphate

diphosphohydrolase-2 is the ecto-ATPase of type I cells in taste

buds. J. Comp. Neurol. 497, 112

88 Rong, W. et al. (2000) P2X purinoceptor-mediated excitation of

trigeminal lingual nerve terminals in an in vitro intra-arterially

perfused rat tongue preparation. J. Physiol. 524, 891902

89 Bobbin, R.P. and Thompson, M.H. (1978) Effects of putativetransmitters on afferent cochlear transmission. Ann. Otol. Rhinol.

Laryngol. 87, 185190

90 Kujawa, S.G. et al. (1994) Effects of adenosine 50-triphosphate and

related agonists on cochlear function. Hear. Res. 76, 87100

91 Robertson,D. andPaki,B. (2002)A role forpurinergic receptorsat the

inner hair cell-afferent synapse? Audiol. Neurootol. 7, 6267

92 Sueta, T. et al. (2003) Purinergic receptors in auditory

neurotransmission. Hear. Res. 183, 97108

93 Housley, G.D. et al. (1999) Expression of the P2X2 receptor subunit of

the ATP-gated ion channel in the cochlea: implications for sound

transduction and auditory neurotransmission. J. Neurosci. 19,

83778388

94 Jagger, D.J. and Housley, G.D. (2003) Membrane properties of type II

spiral ganglion neurones identified in a neonatal rat cochlear slice. J.

Physiol. 552, 525533

95 Yukawa, H. et al. (2005) Acute effects of glucocorticoids on ATP-induced Ca2+ mobilization and nitric oxide production in cochlear

spiral ganglion neurons. Neuroscience 130, 485496

96 Cho, H. et al. (1997) Extracellular ATP-induced Ca2+ mobilization of

type I spiral ganglion cells from the guinea pig cochlea. Acta

Otolaryngol. 117, 545552

97 Ito,K. and Dulon,D. (2002) Nonselectivecation conductanceactivated

by muscarinicand purinergicreceptors in ratspiral ganglion neurons.

Am. J. Physiol. Cell Physiol. 282, C1121C1135

98 Nikolic, P.et al. (2003) Expression of the P2X7 receptor subunit of the

adenosine 50-triphosphate-gated ion channel in the developing and

adult rat cochlea. Audiol. Neurootol. 8, 2837

99 Housley, G.D. and Ryan, A.F. (1997) Cholinergic and purinergic

neurohumoral signalling in the inner ear: a molecular physiological

analysis. Audiol. Neurootol. 2, 92110

100 Jarlebark, L.E. et al. (2000) Immunohistochemical localization of

adenosine 50-triphosphate-gated ion channel P2X2 receptor

subunits in adult and developing rat cochlea. J. Comp. Neurol.

421, 289301

101 Wangemann, P. (2006) Supporting sensory transduction: cochlear

fluid homeostasis and the endocochlear potential. J. Physiol. 576,

1121

102 White, P.N. et al. (1995) Quinacrine staining of marginal cells in the

stria vascularis of the guinea-pig cochlea: a possible source of

extracellular ATP? Hear. Res. 90, 97105

103 Munoz, D.J. et al. (2001) Vesicular storage of adenosine triphosphatein the guinea-pig cochlear lateral wall and concentrations of ATP in

theendolymph during sound exposure andhypoxia.Acta Otolaryngol.

121, 1015

104 Wangemann, P. (1996)Ca2+-dependent release of ATPfrom the organ

of Corti measured with a luciferin-luciferase bioluminescence assay.

Audit. Neurosci. 2, 187192

105 Thorne, P.R. et al. (2004) Purinergic modulation of cochlear partition

resistance and its effect on the endocochlear potential in the guinea

pig. J. Assoc. Res. Otolaryngol. 5, 5865

106 Vlajkovic, S.M. et al. (1998) Ecto-nucleotidases terminate purinergic

signalling in the cochlear endolymphatic compartment. Neuroreport

9, 15591565

107 Marcus, D.C. et al. (1998) Protein kinase C mediates P2U purinergic

receptor inhibition of K+ channel in apical membrane of strial

marginal cells. Hear. Res. 115, 8292

108 Sage, C.L. and Marcus, D.C. (2002) Immunolocalization of P2Y4 andP2Y2 purinergic receptors in strial marginal cells andvestibular dark

cells. J. Membr. Biol. 185, 103115

109 Ashmore, J. (2008) Cochlear outer hair cell motility. Physiol. Rev. 88,

173210

110 Zhao, H.B. et al. (2005) Gap junctional hemichannel-mediated ATP

release and hearing controls in the inner ear. Proc. Natl. Acad. Sci. U.

S. A. 102, 1872418729

111 Housley, G.D. et al. (1995) Purinergic modulation of outer hair cell

electromotility. In Active Hearing (Flock, A . et al., eds), pp. 221238,

Pergamon

112 Housley, G.D. et al. (1992) Localization of cholinergic and purinergic

receptors on outer hair cells isolated from the guinea-pig cochlea.

Proc. Biol. Sci. 249, 265273

113 Wang, J.C. et al. (2003) Noise induces up-regulation of P2X2 receptor

subunit of ATP-gated ion channels in the rat cochlea. Neuroreport 14,

817

823114 Szucs, A. et al. (2004) Differential expression of purinergic receptor

subtypes in the outer hair cells of the guinea pig. Hear. Res. 196, 27

115 Mammano, F.etal. (1999) ATP-InducedCa2+ release in cochlear outer

hair cells: localization of an inositol triphosphate-gated Ca2+ store to

the base of the sensory hair bundle. J. Neurosci. 19, 69186929

116 Dulon, D. et al. (1993) Characterization of Ca2+ signals generated by

extracellular nucleotides in supporting cells of the organ of Corti. Cell

Calcium 14, 245254

117 Dulon, D. (1995) Ca2+ signalling in Deiters cells of the guinea-pig

cochlea: active process in supporting cells? In Active Hearing (Flock,

A . et al., eds), pp. 195207, Pergamon

118 Bobbin, R.P. (2001) ATP-induced movement of the stalks of isolated

cochlear Deiters cells. Neuroreport 12, 29232926

119 Munoz, D.J. et al . (1995) Adenosine 50-triphosphate (ATP)

concentrations in the endolymph and perilymph of the guinea-pig

cochlea. Hear. Res. 90, 119

125120 Winslow, R.L. and Sachs, M.B. (1987) Effect of electrical stimulation

of the crossed olivocochlear bundle on auditory nerve response to

tones in noise. J. Neurophysiol. 57, 10021021

121 Ylikoski, J.etal. (1993) Expression patterns of neurotrophin and their

receptor mRNAs in the rat inner ear. Hear. Res. 65, 6978

122 Salih, S.G. et al. (1998) P2X2 receptor subunit expression in a

subpopulation of cochlear type I spiral ganglion neurones.

Neuroreport 9, 279282

123 Huang, L.C. et al. (2005) Developmental regulation of neuron-specific

P2X3 receptorexpression in the rat cochlea.J. Comp. Neurol. 484, 133

143

124 Huang, L.C.et al. (2006) Developmentally regulated expression of the

P2X3 receptor in the mouse cochlea. Histochem. Cell Biol. 125, 681

692


139


13/14

125 Greenwood, D. et al. (2007) P2X receptor signaling inhibits BDNF-

mediated spiral ganglion neuron development in the neonatal rat

cochlea. Development 134, 14071417

126 Tritsch, N.X. et al. (2007) The origin of spontaneous activity in the

developing auditory system. Nature 450, 5055

127 Forsythe, I.D. (2007) Hearing: a fantasia on Kollikers organ. Nature

450, 4344

128 Tang, W. et al. (2008) Pannexins are new molecular candidates

for assembling gap junctions in the cochlea. Neuroreport 19, 1253

1257

129 Marziano, N.K. et al. (2003) Mutations in the gene for connexin 26(GJB2) that cause hearing loss have a dominant negative effect on

connexin 30. Hum. Mol. Genet. 12, 805812

130 Jagger, D.J. and Forge, A. (2006) Compartmentalized and signal-

selective gap junctional coupling in the hearing cochlea. J. Neurosci.

26, 12601268

131 Piazza, V. et al. (2007) Purinergic signalling and intercellular Ca2+

wave propagation in the organ of Corti. Cell Calcium 41, 7786

132 Gale, J.E. et al. (2004) A mechanism for sensing noise damage in the

inner ear. Curr. Biol. 14, 526529

133 Lahne, M. and Gale, J.E.(2008) Damage-induced activation of ERK1/2

in cochlear supporting cells is a hair cell death-promoting signal

that depends on extracellular ATP and calcium. J. Neurosci. 28,

49184928

134 Khan, A.F. et al. (2007) Nucleoside transporter expression and

adenosine uptake in the rat cochlea. Neuroreport 18, 235239

135 Vlajkovic, S.M. et al. (2007) Differential distribution of adenosinereceptors in rat cochlea. Cell Tissue Res. 328, 461471

136 Ramkumar, V. et al. (2004) Noise induces A1 adenosine receptor

expression in the chinchilla cochlea. Hear. Res. 188, 4756

137 Ramkumar, V.et al. (1994) Identification of A1 adenosine receptors in

rat cochlea coupled to inhibition of adenylyl cyclase. Am. J. Physiol.

267, C731C737

138 Ford, M.S. et al. (1997) Up-regulation of adenosine receptors in the

cochlea by cisplatin. Hear. Res. 111, 143152

139 Whitworth, C.A. et al. (2004) Protection against cisplatin ototoxicity

by adenosine agonists. Biochem. Pharmacol. 67, 18011807

140 Blazynski, C. (1990) Discrete distributions of adenosine receptors in

mammalian retina. J. Neurochem. 54, 648655

141 Rey, H.L. and Burnside, B. (1999) Adenosine stimulates cone

photoreceptor myoid elongation via an adenosine A2-like receptor.

J. Neurochem. 72, 23452355

142 Alfinito, P.D.et al. (2002) Adenosine A2a receptor-mediated inhibitionof rodopsin mRNA expression in tiger salamander.J. Neurochem. 83,

665672

143 Greenwood, D. et al. (1997) Expression of the P2X2 receptor subunit

of the ATP-gated ion channel in the retina. Neuroreport 8, 1083

1088

144 Cowlen, M.S. et al. (2003) Localization of ocular P2Y2 receptor gene

expression by in situ hybridization. Exp. Eye Res. 77, 7784

145 Fries, J.E. et al. (2004) Expression of P2Y1, P2Y2, P2Y4, and P2Y6receptor subtypes in the rat retina. Invest. Ophthalmol. Vis. Sci. 45,

34103417

146 Pintor, J. et al. (2004) Immunolocalisation of P2Y receptors in the rat

eye. Purinergic Signal. 1, 8390

147 Wheeler-Schilling, T.H. et al. (2000) Expression of purinergic

receptors in bipolar cells of the rat retina. Brain Res. Mol. Brain

Res. 76, 415418

148 Fries, J.E. et al. (2004) Distribution of metabotropic P2Y receptors inthe rat retina: a single-cell RT-PCR study. Brain Res. Mol. Brain Res.

130, 16

149 Ward, M.M. et al. (2008) Localization and possible function of P2Y4receptors in the rodent retina. Neuroscience 155, 12621274

150 Kvanta, A. et al. (1997) Localization of adenosine receptor messenger

RNAs in the rat eye. Exp. Eye Res. 65, 595602

151 Yaar, R. et al. (2002) Activity of the A3 adenosine receptor gene

promoter in transgenic mice: characterization of previously

unidentified sites of expression. FEBS Lett. 532, 267272

152 Wheeler-Schilling, T.H. et al. (2001) Identification of purinergic

receptors in retinal ganglion cells. Brain Res. Mol. Brain Res. 92,

177180

153 Ishii, K. et al. (2003) Neuron-specific distribution of P2X7 purinergic

receptors in the monkey retina. J. Comp. Neurol. 459, 267277

154 Brandle, U. et al. (1998) Expression of the P2X7-receptor subunit in

neurons of the rat retina. Brain Res. Mol. Brain Res. 62, 106109

155 Franke, H. et al. (2005) P2X7 receptor-mRNA and -protein in the

mouse retina; changes during retinal degeneration in BALBC rds

mice. Neurochem. Int. 47, 235242

156 Shigematsu, Y. et al. (2007) Distribution of immunoreactivity for

P2X3, P2X5, and P2X6-purinoceptors in mouse retina. J. Mol.

Histol. 38, 369371

157 Yazulla, S. and Studholme, K.M. (2004) Vanilloid receptor like 1

(VRL1) immunoreactivity in mammalian retina: colocalization with

somatostatin and purinergic P2X1 receptors. J. Comp. Neurol. 474,407418

158 Uckermann, O.etal. (2005) The glucocorticoidtriamcinolone acetonide

inhibits osmotic swelling of retinal glial cells via stimulation of

endogenous adenosine signaling. J. Pharmacol. Exp. Ther. 315,

10361045

159 Li, Y. et al. (2001) Muller cell Ca2+ waves evoked by purinergic

receptor agonists in slices of rat retina. J. Neurophysiol. 85, 986994

160 Pannicke, T.et al. (2000) P2X7 receptors in Muller glial cells from the

human retina. J. Neurosci. 20, 59655972

161 Reifel Saltzberg, J.M. et al. (2003) Pharmacological characterization

of P2Y receptor subtypes on isolated tiger salamander Muller cells.

Glia 42, 149159

162 Keirstead, S.A. and Miller, R.F. (1997) Metabotropic glutamate

receptor agonists evoke calcium waves in isolated Muller cells.

Glia 21, 194203

163 Bringmann, A. et al. (2002) Activation of P2Y receptors stimulatespotassium and cation currents in acutely isolated human Muller

(glial) cells. Glia 37, 139152

164 Pannicke, T. et al. (2001) Electrophysiological alterations and

upregulation of ATP receptors in retinal glial Muller cells from

rats infected with the Borna disease virus. Glia 35, 213223

165 Fries, J.E. et al. (2005) Identification of P2Y receptor subtypes in

human Muller glial cells by physiology, single cell RT-PCR, and

immunohistochemistry. Invest. Ophthalmol. Vis. Sci. 46, 30003007

166 Innocenti, B. et al. (2004) ATP-induced non-neuronal cell

permeabilization in the rat inner retina. J. Neurosci. 24, 85778583

167 Morigiwa, K. et al. (2000) Neurotransmitter ATP and cytokine

release. Nippon Yakurigaku Zasshi 115, 185192

168 Uckermann, O.etal. (2005) ADPbS evokes microglia activation in the

rabbit retina in vivo. Purinergic Signal. 1, 383387

169 Kawamura, H. et al. (2003) ATP: a vasoactive signal in the pericyte-

containing microvasculature of the rat retina. J. Physiol. 551, 787799

170 Sugiyama, T. et al. (2005) Regulation of P2X7-induced pore formation

and cell death in pericyte-containing retinal microvessels. Am. J.

Physiol. Cell Physiol. 288, C568C576

171 Collison, D.J. et al. (2005) Potentiation of ATP-induced Ca2+

mobilisation in human retinal pigment epithelial cells. Exp. Eye

Res. 80, 465475

172 Friedman, Z. et al. (1989) Human retinal pigment epithelial cells in

culture possess A2-adenosine receptors. Brain Res. 492, 2935

173 Gregory, C.Y. et al. (1994) Stimulation of A2 adenosine receptors

inhibits the ingestion of photoreceptor outer segments by retinal

pigment epithelium. Invest. Ophthalmol. Vis. Sci. 35, 819825

174 Ryan, J.S. et al. (1999) Purinergic regulation of cation conductances

and intracellular Ca2+ in cultured rat retinal pigment epithelial cells.

J. Physiol. 520, 745759

175 Tovell, V.E. and Sanderson, J. (2008) Distinct P2Y receptor subtypesregulate calcium signaling in human retinal pigment epithelial cells.

Invest. Ophthalmol. Vis. Sci 49, 350357

176 Peterson, W.M. et al. (1997) Extracellular ATP activates calcium

signaling, ion, and fluid transport in retinal pigment epithelium. J.

Neurosci 17, 23242337

177 Stellwagen, D. et al. (1999) Dynamics of retinal waves are controlled

by cyclic AMP. Neuron 24, 673685

178 Paes-de-Carvalho, R.et al. (2003) Adenosine regulates the survival of

avian retinal neurons and photoreceptors in culture.Neurochem. Res.

2

Purinergic Receptors in Special Scences

Documents

Transcript of Purinergic Receptors in Special Scences