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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

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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


GPR65 (TDAG8)To 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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