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Table of Contents
List of Abbreviations and Acronyms..............................................................................................4
The low concentrations of oxygen in the muscles and joints primarily causes anaerobic
respiration and lactic acid build up in the synoviocytes, cells lining the articular joints. . Acid
sensing proteins respond to acidic conditions in extracellular spaces and may play a role in
the development and pathology of rheumatoid arthritis involving diverse signaling and
cellular functional responses. Determination of the exact signaling mechanism and expression
of the acid sensing proteins may assist in developing management options for rheumatoid
arthritis................................................................................................................................................6
Hypothesis.........................................................................................................................................6
Objective............................................................................................................................................6
Specific Objectives...................................................................................................6
Literature Review.............................................................................................................................7
Acid Sensing Ion Channels (ASICs)...............................................................................................9
ASIC3 co-expression with two nociceptive ion channels.........................................12
ASIC3 expression in small muscle afferents............................................................12
Metaboreception and the axon reflex.....................................................................12
Modulation by interacting proteins ........................................................................15
Modulation by RF-amide Neuropeptides.................................................................15
G- Protein coupled receptors (GPCRs)........................................................................................16
Transient receptor potential cation channel subfamily V member 1(TRPV1).......................17
The structure of TRPV1 consists of 6 trans-membrane domains. At the aminoterminal there are sequences that mediate the CaM and PIP2 signalling pathways.
..............................................................................................................................18Functionality .........................................................................................................19
Sensitization and desensitization...........................................................................19
Rheumatoid arthritis (RA)............................................................................................................22
Conclusion .....................................................................................................................................23
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List of Abbreviations and Acronyms
7TM 7 transmembrane receptors
ASIC1 Acid-Sensing Ion Channel 1
ASIC3 Acid sensing ion channel
ASICs Acid sensing ion channels
ASlC2 Acid sensing ion channel
ASlC4 Acid sensing Ion channel
ATP Adenosine triphosphate
Ca2+ calcium ion
CGRP calcitonin gene-related peptide
CIPP Channel-interacting PDZ protein
DRG Dorsal root ganglion
FLS Fibroblast - like synoviocytes
GPCRs G- protein coupled receptors
GPLR G protein-linked receptors
GRK G protein coupled receptors kinase
MAGI-1b membrane-associated guanylate kinase with inverted orientation
protein-1
MAPK Mitogen-activated protein kinase
mRNA messenger ribonucleic acid
Na+ sodium ion
NF200 Neurofilament 200
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NGF Nerve growth factor
NHERF-1 Na/H exchange regulatory factor-1
NPAF Neuropeptide FF/AFReceptors
NPFF Neuropeptide FF-amide peptide precursor
P2X3 P2X purinoceptor 3
PGE2 Prostaglandin E2
PICK1 protein interacting with C-kinase 1
PSD-95 postsynaptic density protein 95
RA Rheumatoid arthritis
RANTES Regulated on activation normal T cell expressed and secreted
TRPV1 The transient receptor potential cation channel subfamily V member
1
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The low concentrations of oxygen in the muscles and joints primarily causes anaerobic
respiration and lactic acid build up in the synoviocytes, cells lining the articular joints. . Acid
sensing proteins respond to acidic conditions in extracellular spaces and may play a role in
the development and pathology of rheumatoid arthritis involving diverse signaling and
cellular functional responses. Determination of the exact signaling mechanism and expression
of the acid sensing proteins may assist in developing management options for rheumatoid
arthritis.
Hypothesis
Acid sensing proteins are expressed in human synoviocytes and contribute to the pathology
of rheumatoid arthritis.
Objective
To determine the pathological impact of acid sensing on proteins in rheumatoid arthritis
Specific Objectives
a. Measure the expression of Acid Sensing Proteins in normal and RA human
synoviocytes.
b. Measure specific acid induced cell signaling and functional response in
synoviocytes.
c. Determine the effects of Acid Sensing Proteins inhibition on pathological responses
of synoviocytes.
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Literature Review
Introduction
Rheumatoid arthritis (RA) is a symmetrically distributed disorder that is systemic
autoimmune and chronic whose primary effect is on the joints of the feet and hands . Estimates on
the pervasiveness of RA point to 0.5-1.5 percent of the entire global population according to
Kobelt and Johnson (2008). Nonetheless, its common occurrence is in the ages starting fifty
onwards although it can affect people at any ages especially those past the thirty year mark .
Indeed, there are numerous theories whose credibility is indisputable, linking ageing and RAs
onset. Nevertheless, the free radical theory of ageing is predominantly popular among all of them .
The theory surmises that an accumulation of free radicals occurs throughout a lifespan while the
immune system functions to inhibit the accumulation .
On the other hand, further theoretical elucidations on RAs development in females with
infertility complexities point to low progesterone and oestrogen levels among them due to their
perceived frequent RA development in comparison to their counterparts whose progesterone and
oestrogen levels are normal . Besides, Temprano et al (2011) contend that pregnancy lessens RAs
activity and momentarily restores normal joint capsule function during gestation. The frequency of
theories attempting to explain RAs development leads Clancy et al (2011) to term it a homeostatic
imbalance that is normally termed an autoimmune disorder with unclear aetiology yet all in its
progressiveness and severity.
RAs characterization entails synovial cartilage and bone destruction and inflammation
whose mediation is by prominent tumour-like synovial fibroblasts referred to as pannus expansion
. Active synovium may need higher consumption of oxygen metabolically and joints that are
chronically inflamed produce increased pressure following the huge joint effusion amount and the
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consequent reduced supply of blood . Consequently, there are suggestions that the existence of
rheumatoid synovial microenvironments is normally under hypoxic situations .Acttually studies in
the past indicate that rheumatoid SFs are scidid, hypoxic and are chaaterised by increased lactae
concentration anaerobic (Jurado, et al., 2008) his exhibits that an alteration to anaerobic
metabolism happens in hypoxic synovium
Several studies suggests that fibroblast-like synoviocytes (FLS) actively participate in RAs
progression . Nonetheless, despite the production of MMPs and inflammatory cytokines by FLS
are profuse in SF and the rheumatoid synovial microenvironments being hypoxic few studies
investigate the role of acid sensing proteins in the development of RA (Jurado, et al., 2008).
Cellular mechanisms for the testing of amino acids and proteins emerge to which suggests
a role for each of the intracellular proteins. In additions, transporters of specific amino acids have
a role in determination of the testing facilities. Determination of the exact signaling mechanism
and expression of the acid sensing proteins may assist in developing management options for
rheumatoid arthritis. The role played by cytokines in the process cannot be downplayed with TNF,
IL-1 and IL-6 being the most notable cytokines. These cytokines also enhance the up regulation of
adhesion molecules, induction of the inflammatory response and its mediators and activation of the
osteoclasts apart from being chemotactic.
In RA, CD4+ T cells, macrophages, and B cells intrude the synovium and at times their
organisation into secretive lymphoid combines with germinal centres . The intimal linings
hyperplasia is a result of marked rise in FLS and macrophage-like synoviocytes. In addition,
degradative enzymes that are locally expressed including serine proteases, aggrecanases and
metalloproteinases destruct the articular structures by digesting the extracellular matrix .
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Figure 1. Comparing the normal and inflamed joints
Source: Rheumatory Arthritis (2012)
Acid Sensing Ion Channels (ASICs)
Lamb, (2012) states that fluctions in nutrients differ from the normal portion to cancer cells
and therefore may lead to future methods of cancer therapy. He suggests that use of nutitional
sources can help cancer cells ready to tear up tomor to separate the tomor from the good cells.
ASICs are cation channels that conduct and are permeable to Na+ at low rates and are
activated by extracellular protons. However, ASC1a shows low calcium ion permeability . These
channels are voltage insensitive/independent and occur in the neurons. There occur five major
proteins of this family which are encoded by four genes recognised as ASIC1, ASIC2, ASIC3, and
ASIC4. Out of the five proteins of ASICs genes, three of the transcribed proteins form ion
channels, while the remaining two proteins are splice variants. ASCIs are expressed in the
peripheral nervous system (PNS) while in the central nervous system the subunits ASlC1a, 2a and
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4 are expressed. The ASICs mRNA is located outside the sensory neurons within the ganglia with
the exception of ASIC3 which is found within the sensory neurons.
Figure 2: ASIC family of ion channels: ACCN1?? ACCN2?? ARE THEY CORRECT IN THIS
FIGURE? .
The activation of ASICs is mainly through the action of extracellular protons but ASIC1
and ASIC2 in particular, do not rely on the acidic pH formed by an increased H+ concentration for
activation. Their activity and major characteristics are however achieved via association with other
isoforms to form an active protein.
Structurally similar to degenerins, ASICs were thought to be mechanosensitive ion
channels degenerins , as they were expressed as mechanosensory specific skin endings in rodents .
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Behavioural changes in touch sensitivity were noted in ASIC knockout mouse models as
compared to others, .
Trimeric in nature, ASICs are made up of a combination of different subunits. The subunit
ASIC2b is non-functional on its own but is important in modulating channel activity when forming
part of a heteromultimers. The ASIC4 subunit, on the other hand, has no known function.
When the extracellular pH drops as a result of a high concentration of protons, ASICs are
opened . The degenerin super family of ion channels, in which ASICs fall, are epithelial sodium
channels , that are specific to sodium ions and are inhibited in function by the diuretic drugs such
as amiloride. They are membrane spanning proteins that produce two regions with a large
extracellular loop and an intracellular amino and terminal carboxyl groups. To form a functional
ion channel, multiple ASICs subunits must assemble.
ASIC1a is unique from the other forms in that it allows for the permeability of Ca2+in
addition to Na+ thereby additionally allowing the entry of Ca2+ into the neurons. This however only
occurs when the protein is in its homomeric form. Extracellular calcium ions can inhibit or
stimulate the ion channels and thus also act in the regulation of their activity. The displacement of
Ca2+ by H+ leads to the activation of ASIC3. The ions are displaced from a high affinity Ca2+
binding site located extracellular of the open pore . Variations of physiological pH thus play a role
in the activation of ASICs. A transient inward triggered by the positively charged ions causes a
rapid desensitisation and due to this property, ASICs are able to detect dynamic fluctuations in the
pH of the system.
As a functional role, ASIC3 during episodes of ischemic pain sense changes in the pH of
the system that lead to lactic acidosis. This is due to the generation of large fluxes in current at the
dorsal root ganglion of the sensory neurons that supply the nervous impulses to the heart , where
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angina occurs. Also, small changes in the extracellular pH occurring in muscles due to metabolic
stress, pH 7.4 to 7.0, are detected and responded to.
The co-localisation of ASIC3 and ASIC2 occurs in the dorsal root ganglion sensory and
these proteins are more commonly found in larger . However, when ASIC3 is co-expressed with
calcitonin gene-related peptide (CGRP), it is found in large and small trigeminal ganglion
neurons .
ASIC3 co-expression with two nociceptive ion channels
Characterise nociceptive neurons carrying ASICs, P2X3 and ATP- gated ion channels were co-
expressed . These were thought to be pain transducers and a capsaicin receptor of the transient
receptor potential cation channel subfamily V member 1 (TRPV1) . An observed overlap between
ASIC3 and P2X3 was noted, with co-expressed cells being large with P2X3 positive cells staining
equally positive for ASIC3. This point towards there being a population of co-expressed sensory
neurons with overlaps also noted between ASIC3 and TRPV1.
ASIC3 expression in small muscle afferents
A necessitated low blood flow to the muscles may result in ischemic pain. However, as
noted during thermoregulation and response to adrenaline boosts in the flight or fright response,
reduced blood flow to the skin is without any pain.
Metaboreception and the axon reflex
With a small change in pH, especially due to lactic acidosis build up during anaerobic
metabolism in the muscles, causing the ASCIs to open up , , metaboreception is considered to be a
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subset of nociception . Thus, compensatory changes in the peripheral tissues are triggered by low
activity levels while high activity levels trigger the sensation of pain . To be considered as a sensor
for ischemic pain, ASIC3 should ideally be located in the dorsal root ganglion afferents of the
cardiac muscles which again should be enriched by sensory neurons that supply it as compared to
the skin as ischemic pain is characteristic to muscles other than the skin.
The overlap between ASIC3 and the vasodilator peptide CGRP is noted in a majority of
AISC3 positive sensory neurons that innervate the muscles that also co-express CGRP. Lightly
myelinated axons fibres co-express the three markers due to their expression of NF200, a marker
of myelinated axons (Jurado, et al., 2008).
The axon reflex, caused by the peripheral release of CGRP occurs due to vasodilation and
extrvasations due to the activation of C fibres . The co-expression of all three proteins; ASIC3,
TRPV1 and CGRP, on the afferent vessels of the arterial muscle might point to the fact that all
three function as sensors and effectors in regulating localised flux of blood in response to elevated
lactic acid levels and rising temperatures of the muscle. This co-expression thus assists the cells in
detecting a broad range of acid sensitivities.
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Figure 3: ASICs as displayed in the primary afferent nociceptors and in the spinal cord neurons
(Molliver et al., 2005)
In the central and peripheral nervous systems, ASIC1 and ASIC3, respectively, play key
roles together with extracellular modulators and interacting proteins. The activity of ASIC3 is up-
regulated by activators of the protein kinase C (PKC) pathway which are released during
peripheral inflammation that leads to an elevation of mRNA transcript levels of ASIC3 in the
dorsal root ganglion and the spinal cord. Protons released at either the pre or post synaptic
membranes could activate .
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Modulation by interacting proteins
ASICs and their interacting protein have been associated with the function to control
surface expression and the sub cellular distribution of ion channels.
The PDZ binding motif of ASICs at their C termini interacts with several other PDZ motif
containing proteins. The interaction between protein and C-kinase 1 (PICK1) that takes a part in
the up-regulation of ASICs by protein kinase C , co-localizes and associates in the nervous system
especially with ASIC1 and ASIC2 .
ASIC3 association with proteins such as Channel-interacting PDZ protein (CIPP) increases
or decreases the rate and level of surface expression of the ion channel without causing a
significant change in its properties. This is due to heterologous expression systems . Integral
membrane proteins such as stomatin expressed in sensory neurons associate with ASIC1a,
ASIC2a, and ASIC3 and function to reduce the ion channel current and to increase the rate of
desensitization of the channels .
Modulation by RF-amide Neuropeptides
The potency of the H+ gated ion channels current by causing an increase in the peak
amplitude or by slowing the inactivation of the ASICs is directly modulated by FMRF-amide at pH
7.4 and structurally related peptides on the channels .The neuropeptide FF/AF receptors (NPAF)
and the neuropeptide FF-amide peptide precursor (NPFF), are expressed in the central nervous
system and especially so in the spinal cord where they are in higher levels and their expression is
enhanced during chronic inflammation. This modulation is in response to noxious acidosis that
may occur when the channel is closed .
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GPR4, GPR65 and GPR68 are proton sensing receptors. The cells that express GPR65
increase the level of cAMP (Lamb, 2012) in response to the neutral to the acidic extracellular pH.
Due to this, cAMP accumulation is suppressed by pschosines inhibition of PH dependent effects
in GPR68 and GPR4 expressing cell. This has also been observed to indicate that pschosine acts as
an inverse agonist of GPR4, GPR65, and GPR68.
Chemokines play a vital role in the pathology and treatment of arthritis by mediating
chemotaxis and activation of the leukocytes in an immune response mechanism . Receptor
antagonists to monocyte chemoattractant protein-1 (MCP-1) and RANTES affect the progression
of the disease towards a positive outcome . These two chemokines and their receptors thus have an
important role in arthritis by initiating and maintaining the local inflammatory process that
enhances the recruitment of both monocytes and lymphocytes into the joints . Chemokine and 2
adrenergic receptors are examples of GPCRs which are turned off by kinases of the GRK.
The GRK kinases switch off the receptors leading to a loss of the receptors responsiveness
to its ligand, in a process referred to as homologous desensitization. The residues of
serine/threonine on the carboxy tail of the intracellular loops of the receptor are phosphorylated by
the kinases. The phosphorylated receptor residues act as docking sites for inhibitory proteins
arrestins which potentially inhibit the coupling of the receptor and the G proteins . GRKs receptor
substrates are embraced in a wide variety of functions including neurotransmission and immune
responses, used to transduce signals through various intracellular second messengers .
Transient receptor potential cation channel subfamily V member 1(TRPV1)
The capsaicin and vanilloid receptor 1 protein is encoded by the TRPV1gene in humans.
This group of ion channels detects and regulates body temperature, and also provides sensations of
high temperature (heat) and pain (nociception). Structurally, TRPV1 is 838 amino acids long with a
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molecular weight of 95kDa. It is 6 transmembrane domains, a C-terminal cytosolic region that is 132
amino acids long, and an N-terminal region that is 432 amino acids long (Fig. 2).
Figure 5: TRPV1 structure.
The structure of TRPV1 consists of 6 trans-membrane domains. At the amino terminal there are sequences
that mediate the CaM and PIP2 signalling pathways.
The TRPV1 is widely distributed across many tissues and is activated in a polymodal manner by
both chemical and physical stimulators. Different TRPV1 activators are tabulated below.
Table 1: Physical and chemical activators of TRPV1
Activator Examples
Vanilloids Capsaicin, olvanil, resiniferatoxin
Lipids Anandamide, oleoyldopamine, endocannabinoid), N-arachidonoyl Dopamine, 18
20 carbon N-acylethanolamines, 12-hydroperoxyeicosatetraenoic acid
Protons H+
Cations K+, Rb+, Cs+, Na+ and Li+ ions
Heat
18
Plasmamembrane
CaM
PIP2
TRP
box
NH4
COOH
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Voltage
Source:
Functionality
The TRPV1 cation channel is non selective in nature and can be ideally stimulated by a
wide range and different types of endogenous and exogenous stimuli , such as acidic conditions
(increased H+ concentration), N-arachidonoyl dopamine, vanilloids, like capsaicin and heat , that
leads to a painful and burning sensation . Located in the PNS nociceptive neurons, TRPV1
receptors transmit and modulate pain (nociception) as well as play a role in the integration of
diverse painful stimuli .
Sensitization and desensitization
During tissue damage, injury and in the inflammation process, prostaglandins and bradykinin, are
released as inflammatory mediators into the system and they in turn lead to an increase in
nociceptors sensitivity to noxious stimuli. This manifests as an increased sensitivity to the stimuli
of pain or to the increased sensation of pain in response to non-pain stimuli. The phospholipase C
(PLC) pathway is activated by these pro-inflammatory agents leading to the phosphorylation of
TRPV1 by PKC leading to its sensitization. The cleavage of phosphatidylinositol 4, 5-bisphosphate
(PIP2) by PLC results in then disinhibiton or TRPV1 and consequently contributes to the
sensitivity of TRPV1 to noxious stimuli.Desensitization may however occur when a long exposure
to the stimuli is affected due to decreased TRPV1 activity mediated by an increased intracellular
Ca2+ due to its influx from the extracellular space.
TRPV1 synthesis occurs in the dorsal root ganglia sensory neurons which are then
transported along the central and peripheral axons to the spinal dorsal horn and to the skin and
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viscera organs, respectively . TRPV1 is critical for a number of sensory issues in the skin, such as
high temperature (heat), nociception or pain sensation, inflammatory hyperalgesia , allodynia, and
neuropathic nociception (pain) . Capsaicin, used in the management of arthritic pain, works by
temporarily desensitizing the receptor TRPV1 which, is also its only known receptor ,, and by
reducing blood flow in capsaicin sensitive afferents ,
Despite its role in arthritis, the exact mechanisms by which TRPV1 is implicated are not
fully understood. The sensation of pain leads to gene expression of the immediate genes in the
sensory neurons. The extracellular-regulated kinase (ERK) pathway, part of the serine/threonine
protein kinases of the MAPK family, links nocioception to altered gene expression by transducing
the extracellular stimuli into through its signal pathway to achieve an intracellular transcriptional
and post-translational response. After activation by mediators of cellular stress and inflammation,
growth factors and mitogens, MAPK translocates into the nucleus where it binds to transcription
factors and causes the regulation of relevant genes transcription to achieve many cellular activity,
such as proliferation, and production of cytokines and other regulatory response factors during
inflammation . The MAPK exist in numerous isoforms and are activated by a sequence of
upstream phosphorylation and dephosphorylation reactions mediated by kinases, hence forming a
complex biochemical cascade which is critical in the overall regulation of the inflammatory
process .
In respect to arthritis, ERK pathway inhibition results in an attenuated nociception and
inflammation . The duration of arthritis is correlated with increased number ERK positive neurons
in the spinal neurons and also this increase is noted in inflamed joint movement.
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TABLE 2:summary of PH ranges, tissue distribution and inhibitors of acid sensing
proteins.
Rheumatoid arthritis (RA)
This is a long term illness causing inflammation of joints and any surrounding tissues. In
the pathology of rheumatoid arthritis, pro-inflammatory cytokines have been noted due to their
biological function as mediators of inflammation, cell activation and growth factors . The role of
the nervous system in the pathogenesis of rheumatoid arthritis has been shown with the 2
adrenergic receptor antagonist delaying the onset and severity of joint pains and injury in arthritis .
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ASP PH act Expressed in Inhibitor
ASIC1a 6.2-6.8 PNS, brain, retina, taste cells, boneAmiloride,NSAIDs
ASIC1b 5.1-6.2 PNS, taste cells Amiloride
ASIC2a 4.1-5.0 PNS, brain, retina, taste cells, bone Amiloride
ASIC2b N/A PNS, brain, retina, taste cells N/A
ASIC3 6.2-6.7PNS, brain, retina, taste cells, bone, inner ear, lung epithelialcells
Amiloride,NSAIDs
ASIC4 N/A Plow in PNS, brain, spinal cord, retina, pituitary gland, innerear
N/A
TRPV17.4-5.5
CNS , non-neuronal tissues such as keratinocytes, mastcells, hair follicles, smooth muscle, bladder, liver, kidney,spleen and lungs
OGR1 (GPR68)To becompleted
To be completedTo becompleted
G2ATo becompleted
To be completedTo becompleted
GPR65 (TDAG8)To becompleted
To be completedTo becompleted
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Pro-inflammation of the nervous system in rheumatoid arthritis during clinical studies has shown
that the distribution of the synovitis is symmetrical ,
Conclusion
The acid-sensing protein ASIC, G-protein-coupled receptors (GPCRs) and the TRPV1
receptor may play a critical role in the pathogenesis of RA through acid sensing, modulation of
expression and release of hyaluronan, and induction of signalling pathways that aggravate
inflammation. Understanding the molecular mechanisms that underline these processes is
important as it can help to devise novel therapeutic agents for the treatment of RA.
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