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Purinergic Signal. 2010 June; 6(2): 201–209.
Published online 2010 May 20. doi:  10.1007/s11302-010-9183-x
PMCID: PMC2912986

Purinergic signaling in cochleovestibular hair cells and afferent neurons


Purinergic signaling in the mammalian cochleovestibular hair cells and afferent neurons is reviewed. The scope includes P2 and P1 receptors in the inner hair cells (IHCs) of the cochlea, the type I spiral ganglion neurons (SGNs) that convey auditory signals from IHCs, the vestibular hair cells (VHCs) in the vestibular end organs (macula in the otolith organs and crista in the semicircular canals), and the vestibular ganglion neurons (VGNs) that transmit postural and rotatory information from VHCs. Various subtypes of P2X ionotropic receptors are expressed in IHCs as well as P2Y metabotropic receptors that mobilize intracellular calcium. Their functional roles still remain speculative, but adenosine 5′-triphosphate (ATP) could regulate the spontaneous activity of the hair cells during development and the receptor potentials of mature hair cells during sound stimulation. In SGNs, P2Y metabotropic receptors activate a nonspecific cation conductance that is permeable to large cations as NMDG+ and TEA+. Remarkably, this depolarizing nonspecific conductance in SGNs can also be activated by other metabotropic processes evoked by acetylcholine and tachykinin. The molecular nature and the role of this depolarizing channel are unknown, but its electrophysiological properties suggest that it could lie within the transient receptor potential channel family and could regulate the firing properties of the afferent neurons. Studies on the vestibular partition (VHC and VGN) are sparse but have also shown the expression of P2X and P2Y receptors. There is still little evidence of functional P1 (adenosine) receptors in the afferent system of the inner ear.

Keywords: ATP, Adenosine, Mammalian, Inner ear, Cochlea, Vestibular organ, Inner hair cell, Vestibular hair cell, Spiral ganglion, Vestibular ganglion


Purinergic signaling is involved in various important physiological processes of the central nervous system including neurotransmission, neuromodulation, development, survival, and repair of neurons [1, 2]. Purinergic receptors are divided into P2 receptors that bind adenosine 5′-triphosphate (ATP), adenosine 5′-diphosphate (ADP), and other extracellular nucleotides, and P1 receptors that are activated by adenosine. The family of P1 (adenosine) receptors is G-protein-coupled (metabotropic receptors) and signals by inhibiting or activating adenylate cyclase. The P2 (primarily ATP) receptor family is divided into P2X (ionotropic or ligand-gated) and P2Y (metabotropic) receptors. There are several subtypes for P2X (P2X1–P2X7, consecutively) and P2Y (P2Y1–P2Y14, not consecutively) that have different selectivity for agonists/antagonists. P2X receptors are generally believed to be involved in direct neurotransmission/modulation while P2Y receptors are mainly implicated in glia–neuron interactions. Purinergic signaling, principally P2, has also been demonstrated in special sense organs and their primary neurons related to vision, hearing, olfaction, and taste [3], but there still remains a large room for investigation, especially in the vestibular sensory system.

In this article, we review the studies on purinergic signaling in the afferent system of the eighth cranial nerve, i.e., the mammalian cochleovestibular hair cells and afferent neurons. The scope includes P2 and P1 receptors on the inner hair cells (IHCs) of the cochlea, the type I spiral ganglion neurons (SGNs) that convey auditory signals from IHCs, the vestibular hair cells (VHCs) in the vestibular end organs (macula in the otolith organs and crista in the semicircular canals), and the vestibular ganglion neurons (VGNs) that transmit postural and rotatory information from VHCs. The outer hair cells (OHCs) of the cochlea that amplify the movement of the basilar membrane with active motility are out of scope of the present review. Histological expression (mRNA and receptor protein) and physiological effects (in vivo and in vitro) will be discussed along with physiological and developmental implications.

Histological expression (mRNA and receptor protein) of P2 receptors in the cochlear partition (IHC and SGN type I) (Table (Table11)

Table 1
Histological expression (mRNA and receptor protein) of P2 receptors in the cochlear partition


The studies have neither been comprehensive nor consistent. Only P2X2, P2X3, and P2X7 receptors have been investigated, and the results have discrepancy among species and between methods (in situ hybridization and immunohistochemistry). Part of such discrepancy may be due to the age of animals investigated, since transient expression in certain developmental stages has been shown in each subtype (P2X2, P2X3, and P2X7). However, among them, consistent results show that the P2X ionotropic channels are localized at the endolymphatic surface [4], especially at the stereocilia [9], and Na+ influx through these channels was visualized using fluorescence [5]. More specifically, the P2X2 receptor subtype was shown to be localized at the stereocilia of guinea pig hair cells [9], and therefore this may be the dominant P2X subtype.

SGN type I

All seven subtypes (P2X1–P2X7) have been shown to be expressed in adult SGNs. However, some subtypes (P2X1, P2X2, P2X3) showed transiently stronger expression during the time period just before the onset of hearing (P12–P14 in rat), implying their developmental roles [68, 10, 11, 15].

P2 receptor expression can be modulated under environmental influence. Noise-induced upregulation of a certain subtype (P2X2) on the SGNs was reported [18]. Expression of ectonucleotidases (NTPDases) that hydrolyze ATP and ADP has also been reported in specific regions of the cochlea, including vasculature, neurons, hair cells, and supporting cells [19, 20]. Strong expression of NTPDase implies active purinergic signaling at these sites. In addition, differential expression between NTPDase1, which is a nucleoside diphosphatase and triphosphatase, and NTPDase2, which hydrolyzes nucleoside triphosphates preferentially, was observed. Stereocilia and the synaptic regions between IHC and SGN expressed both NTPDase1 and NTPDase2, whereas SGN body principally expressed NTPDase1. NTPDase3, a functional intermediate between NTPDase1 and 2, was also expressed in the cell bodies of the SGNs and the synaptic regions under IHCs [21].

Functional expression of P2 receptors in the cochlear partition

In vivo study

In vivo studies (Table 2) have exclusively been conducted using intracochlear perfusion with guinea pigs. In brief, cochleae of deeply anesthetized animals were opened in a minimally invasive manner and the scala tympani (perilymph) or scala media (endolymph) was perfused with small catheters and pumps. Physiological parameters such as cochlear microphonic (CM), endocochlear potential (EP), summating potential (SP), distortion product otoacoustic emissions (DPOAE), and compound action potentials (CAP) were recorded during perfusion, and the effects of perfused ligands or antagonists were evaluated. Most results indicated suppressive effects of ATP on the above physiological parameters in endocochlear perfusion [22, 23, 25, 27] but with an exception in which ATP analogs increased the endocochlear potential [26]. Moreover, perfusion with ATP antagonists (suramin, cibacron blue, and basilen blue: antagonists not specific for either P2X or P2Y) did not show consistent changes in the cochlear function [24], implying complex effects of P2 receptors in the cochlea. These controversial results can be attributed to simultaneous effects on multiple targets (hair cells, supporting cells, stria vascularis, etc.).

Table 2
In vivo studies on the cochlear partition

In vitro study


Functional P2X and P2Y receptors have first been demonstrated using spectrofluorometry recordings of intracellular calcium during ATP application (Table 3) [28]. Patch-clamp recordings revealed the expression of ionotropic (P2X) cation nonselective conductance mainly localized near the apical region (cuticular plate) of IHCs [29], since ATP-gated current had a larger amplitude and a shorter latency when the puff pipette was located at the cell apex rather than at the synaptic base (see Fig. 8 of [29]). Studies using fluorescent imaging of Na+ influx confirmed the apical location of ionotropic receptors, facing the endolymphatic compartment [4, 5]. To date, there have been few reports on differential expression of P2 receptors along the basilar membrane, i.e., basal, middle, and apical turns. For example, there was no difference in ATP conductance of IHCs among cochlear turns [30].

Table 3
In vitro studies on the cochlear partition

Furthermore, intracellular processes that regulate purinergic signaling have been reported in adult guinea pig IHCs [35, 36]. ATP-induced intracellular Ca2+ responses are likely regulated by a negative feedback mediated by nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and cGMP-dependent protein kinase.

SGN type I

As in IHCs, Ca2+ responses showed functional P2X and P2Y receptors [31], and electrophysiology demonstrated ionotropic (P2X) cation nonselective conductance [32, 33]. Moreover, a large conductance evoked by metabotropic (P2Y) receptors was reported [33]. A more detailed review of ATP-evoked conductances in SGNs will appear in the following section.

Regarding the regulation of ATP-induced intracellular Ca2+ mobilization related to NO, SGNs seem to display a different mechanism as compared to IHCs [37]. In SGNs, NO production due to Ca2+ influx acts in a positive feedback manner, and glucocorticoids have an enhancement effect on this process.

P2 receptors in the vestibular partition (VHC and VGN)

Compared to the cochlear partition, studies in the vestibular partition of mammals have been sparse. No in vivo electrophysiological recordings investigating the role of ATP in the mammalian vestibular organs have been reported. Histological expression of P2 receptor protein or mRNA has not been demonstrated in VHCs but there is one report of functional expression of P2 receptors [38]. In this study, functional P2 receptors were demonstrated in guinea pig VHCs by electrophysiology and Ca2+ responses but a detailed characterization was not completed, e.g., involvement of P2X receptors was evident but that of P2Y receptors remained undetermined. In adult rat VGNs, immunohistochemistry demonstrated P2X1–P2X6 subtypes as in SGNs [14]. However, developmental changes of particular subtypes as observed with SGNs have not yet been demonstrated. As for in vitro physiological studies, Ca2+ responses revealed functional expression of P2X and P2Y receptors [39]. Moreover, we recently characterized electrophysiological properties of ionotropic (P2X) conductance in VGNs (Table 4) [40]. The characteristics of this conductance were similar to those observed in SGNs except that lowering extracellular pH, a procedure to evaluate modulation of the affinity of the ATP-binding site by extracellular protons [2], produced little effects in VGNs as compared to a response augmentation in SGNs [32].

Table 4
P2 conductances in SGN (type I) and VGN

P1 receptors in the inner ear

An immunohistochemical study showed expression of three subtypes of P1 adenosine receptors (A1R, A2AR, and A3R) in both IHCs and SGNs of adult rats [41], but developmental changes of expression have not been reported. No protein or mRNA expression study for P1 receptors has been reported in the vestibular organs.

To date, there is little evidence of functional P1 receptors in the inner ear. In the cochlear partition, perfusion of adenosine in either perilymph or endolymph showed no changes in cochlear physiological parameters such as CAP [23, 25] and no in vitro study has been published. However, Vlajkovic et al. [42] (this issue; see also [43]) provides evidence that A1 receptor activation facilitates recovery from noise-induced hearing loss. In addition, prophylactic treatment with P1 receptor agonists confers otoprotection from noise damage [44, 45]. In the vestibular organs, there has been no in vivo study, and a direct application of adenosine on isolated VGNs in vitro failed to show any electrophysiological effects [40].

Physiological implication


Important developmental roles played by purinergic (P2) receptors have recently been suggested [46, 47]. A specific multimeric combination of receptor subtypes (P2X2–3 and P2X3) was shown to contribute to synaptic reorganization to constitute accurate innervation pattern (SGN type I to IHC and SGN type II to OHC) just before the onset of hearing in rats, by inhibiting BDNF-mediated neuron development [47]. This corresponds to the transient expression of P2X3 receptors reported previously [10, 11]. Another novel discovery is the contribution of purinergic signaling to the spontaneous firing activity of SGNs before the onset of hearing, which is important to neuronal survival and maintenance of tonotopic maps in the brain. It was shown that supporting cells adjacent to IHCs spontaneously release ATP that would depolarize the IHCs and trigger action potentials in the developing SGNs [46].

Signal transduction/modulation in IHC

Endolymph contains nanomolar levels of ATP [48], which is supposed to be derived from a vesicular storage in the lateral wall, i.e., stria vascularis [49], and/or to be released from supporting cells of the organ of Corti [50]. Localization of P2X receptors facing the endolymphatic surface suggests a regulatory role of endolymphatic ATP on the IHC receptor potentials. Indeed, ATP concentration increases in the endolymph during noise exposure [49]. P2X receptors at the apex of IHC may adaptively suppress sound transduction processes, as indicated by several in vivo studies [22, 23, 25].

Neuromodulation in SGN/VGN

Table 4 summarizes P2 conductances in SGN (type I) and VGN. In the two types of neurons of the inner ear, P2X ionotropic conductances share many properties including desensitization characteristics and ion permeability, except ligand preference (the order of response amplitudes to ATP and its analogs) and sensitivity to external pH. The small difference may be due to a distinct subtype configuration that forms different heteromultimeric receptor channels in SGNs and VGNs, although six subtypes (P2X1–P2X6) were identified in both SGNs and VGNs with similar patterns [14]. A preliminary in vitro study also identified a desensitizing (P2X) conductance in SGN type II innervating outer hair cells (OHCs), which had a similar amplitude and a similar desensitization time constant (2 s) with those of type I SGNs [51]. Moreover, it was recently shown that the function of SGN type II as a cochlear afferent can be modulated by ATP [52].

The metabotropic, P2Y-evoked conductance in SGNs has notable properties not reported in other primary sensory neurons of the cranial nerves. This slowly activating nonselective conductance is likely driven by a pore channel that can pass large cations such as NMDG+ and TEA+ [33]. Intriguingly, this large pore channel can also be activated by other metabotropic receptors, i.e., tachykinin receptors (NKR, ligand: substance P) and muscarinic acetylcholine (ACh) receptors (mAChR) as confirmed by mutual desensitization and nonadditive nature of responses. In detail, two different components in ATP-evoked currents were identified in acutely isolated SGNs from the rat cochlea: a rapid ionotropic (P2X) current and a slow metabotropic (P2Y) response. The two components could be isolated using a very short application of ATP. The first (P2X) current was mainly carried by Na+, but the second conductance (P2Y) had a large pore that passed very large cations (see Fig. 5 of [33]). This P2Y conductance shared many characteristics with ACh-evoked (muscarinic) and substance P-evoked conductances including the most effective block by ionomycin pretreatment (see Fig. 9 of [33] and Fig. 4 of [34]). The mechanism of this block remained uncertain, but it is possible that certain intracellular resources mobilized by intracellular calcium release are depleted by ionomycin. Mutual inhibition and nonadditivity of ligand-evoked conductances were demonstrated between each pair of the three ligands, i.e., ATP, ACh, and substance P. (See Fig. 10 of [33] and Fig. 5 of [34].) By these experiments, the P2Y receptor (P2YR)-mediated conductance was demonstrated to share the final effector channel with mAChR and NKR.

The molecular nature of this large-conductance nonspecific channel remains unknown, but this may be a member of the transient receptor potential (TRP) channel family, which has recently attracted researchers’ attention. TRP channels, initially discovered in Drosophila, a fruit fly, form a loosely related superfamily of relatively nonselective cation channels with a diverse ionic selectivity [53, 54]. To date, TRP channels have been found ubiquitously expressed in various cell types also in vertebrates. TRP channels are comprised of six transmembrane segments with intracellular N- and C-terminals. Activation mechanisms are diverse: stimuli concerning vision, taste, olfaction, hearing, touch, thermosensation, and osmosensation, etc. The TRP superfamily, comprised of more than 30 cation channels, is divided into seven subfamilies: canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), polycystin (TRPP), mucolipin (TRPML), ankyrin (TRPA), and NOMPC (TRPN) families [53, 54]. Notably, TRPA1 has been suspected as a component of mechanotransduction channels at the hair bundles of sensory hair cells [55, 56]. In SGNs, TRP receptors have been shown to be expressed in the cell body by immunohistochemistry: TRPV1-6 [5759], TRPC1-7, more intensely in TRPC1 and TRPC3 [60, 61], TRPM1, 2, 3, 6, 7, and 8 [62], TRPML1-3, TRPP2, 3, and 5 [63]. Modified expression of TRPV was reported following cochlear damage. Acoustic damage upregulated expression of TRPV1 in SGNs [64]. Kanamycin intoxication upregulated TRPV1 expression but downregulated TRPV4 expression [65]. Similarly, gentamicin challenge upregulated TRPV1 and 2 expression but downregulated TRPV3 and 4 expression in SGNs [66]. Developmental regulation of TRPC3 expression has recently been shown in the mouse cochlea including SGNs [67].

Among these subfamilies, the most promising candidate for the common effector channel activated by various metabotropic processes in SGNs is the TRPC channel. Indeed, there has been increasing evidence demonstrating TRPC channels as final effectors evoked by various metabotropic processes in other cell types. It has been suggested that mAChRs activate, via G-protein and phospholipase C (PLC), a nonselective cation conductance linked to TRPC5 channels in HEK cells [68]. Similarly, in neuronal PC12D cells, muscarinic receptors (M1mAChR) activated TRPC6 channels, mediated by protein kinase C [69]. In rat cardiomyocytes, P2Y2 channels activated heteromeric TRPC3/7 channels mediated by G-protein and PLC beta [70], explaining the cause of arrhythmia after ischemic damage of cardiac cells. In HEK cells expressing both tachykinin receptors (NK2Rs) and TRPC3 channels, substance P evoked nonselective cation conductance [71]. Finally, both mAChR and P2YR were shown to activate common TRPC7 channels mediated by PLC and diacylglycerol, resulting in calcium influx in human keratinocytes [72]. Therefore, TRPC effector channels can be shared by multiple metabotropic processes evoked by different ligands, and further research targeting this type of TRP channel should be performed in SGNs.

The P2X ionotropic receptors are expected to play a direct neuromodulatory role, cooperating with glutamate receptors, since some reports showed strong expression of this receptor at the synaptic afferent boutons under IHCs [9, 16]. However, the question remains open whether ATP is coreleased with glutamate during exocytosis of the synaptic vesicles in IHCs.

In contrast, the role of the P2Y metabotropic receptors may be diverse, and we recall that these receptors have been shown to be expressed in the SGN perikaryons [33]. The P2Y-activated cation nonselective, depolarizing conductance, can reinforce neuronal excitability at the level of the perikaryon and facilitate the propagation of action potentials along the nerve fibers. Interestingly, it has recently been shown that P2Y receptors, cooperating with a simultaneously evoked P2X conductance, increased the neuronal firing rates in the mammalian cochlear nucleus [73]. Moreover, control of intracellular calcium can modify neuronal survival (trophic effect), and the neurons can recognize environmental pathologic events by sensing dispersed ATP via purinergic receptors (damage confrontation), thereby invoking (so far unknown) self-defense intracellular mechanisms. Finally, sharing a common effector among different metabotropic receptors (P2YR, mAChR, NKR) implies an important role of this cellular process in SGNs, which remains to be elucidated.

Perspectives for future research

As described above, there is increasing evidence showing the importance of purinergic receptors (P2X) in cochlear development but their precise neuromodulatory roles in auditory physiology after cochlear maturation are still unclear. Studies on P2Y receptors in the inner ear are still sparse, and their physiological role also remains to be determined. In particular, the P2Y-associated nonspecific cation channels (TRP channel?), shared by other metabotropic receptors (mAChR and NKR), remain to be identified in SGNs. In the vestibular partition, since only a small number of works have been conducted in VHCs and VGNs, there is a large need of future investigation to identify the physiological role of these receptors in the vestibular system. Histological and functional investigation on the expression of P2 receptors in the vestibular partition (VHC/VGN) would certainly help to understand their role by comparison with the cochlear partition (IHC/SGN). As to P1 receptors, there is convincing evidence for the expression in IHCs and SGNs, with emerging physiological function. It would be of particular interest to see whether adenosine receptors, well known to modulate long-term potentiation (LTP) in central neurons, can also regulate neurotransmitter release in IHCs.

Contributor Information

Ken Ito,

Didier Dulon, rf.mresni@nolud.reidid.


1. Fields RD, Burnstock G. Purinergic signalling in neuron–glia interactions. Nat Rev Neurosci. 2006;7:423–436. doi: 10.1038/nrn1928. [PMC free article] [PubMed] [Cross Ref]
2. North RA. Molecular physiology of P2X receptors. Physiol Rev. 2002;82:1013–1067. [PubMed]
3. Housley GD, Bringmann A, Reichenbach A. Purinergic signaling in special senses. Trends Neurosci. 2009;32:128–141. doi: 10.1016/j.tins.2009.01.001. [PubMed] [Cross Ref]
4. Mockett BG, Housley GD, Thorne PR. Fluorescence imaging of extracellular purinergic receptor sites and putative ecto-ATPase sites on isolated cochlear hair cells. J Neurosci. 1994;14:6992–7007. [PubMed]
5. Housley GD, Raybould NP, Thorne PR. Fluorescence imaging of Na+ influx via P2X receptors in cochlear hair cells. Hear Res. 1998;119:1–13. doi: 10.1016/S0378-5955(97)00206-2. [PubMed] [Cross Ref]
6. Housley GD, Luo L, Ryan AF. Localization of mRNA encoding the P2X2 receptor subunit of the adenosine 5′-triphosphate-gated ion channel in the adult and developing rat inner ear by in situ hybridization. J Comp Neurol. 1998;393:403–414. doi: 10.1002/(SICI)1096-9861(19980420)393:4<403::AID-CNE1>3.0.CO;2-4. [PubMed] [Cross Ref]
7. Jarlebark LE, Housley GD, Thorne PR. Immunohistochemical localization of adenosine 5′-triphosphate-gated ion channel P2X(2) receptor subunits in adult and developing rat cochlea. J Comp Neurol. 2000;421:289–301. doi: 10.1002/(SICI)1096-9861(20000605)421:3<289::AID-CNE1>3.0.CO;2-0. [PubMed] [Cross Ref]
8. Jarlebark LE, Housley GD, Raybould NP, Vlajkovic S, Thorne PR. ATP-gated ion channels assembled from P2X2 receptor subunits in the mouse cochlea. NeuroReport. 2002;13:1979–1984. doi: 10.1097/00001756-200210280-00030. [PubMed] [Cross Ref]
9. Housley GD, Kanjhan R, Raybould NP, Greenwood D, Salih SG, Jarlebark L, Burton LD, Setz VC, Cannell MB, Soeller C, Christie DL, Usami S, Matsubara A, Yoshie H, Ryan AF, Thorne PR. Expression of the P2X(2) receptor subunit of the ATP-gated ion channel in the cochlea: implications for sound transduction and auditory neurotransmission. J Neurosci. 1999;19:8377–8388. [PubMed]
10. Huang LC, Greenwood D, Thorne PR, Housley GD. Developmental regulation of neuron-specific P2X3 receptor expression in the rat cochlea. J Comp Neurol. 2005;484:133–143. doi: 10.1002/cne.20442. [PubMed] [Cross Ref]
11. Huang LC, Ryan AF, Cockayne DA, Housley GD. Developmentally regulated expression of the P2X3 receptor in the mouse cochlea. Histochem Cell Biol. 2006;125:681–692. doi: 10.1007/s00418-005-0119-4. [PubMed] [Cross Ref]
12. Nikolic P, Housley GD, Thorne PR. Expression of the P2X7 receptor subunit of the adenosine 5′-triphosphate-gated ion channel in the developing and adult rat cochlea. Audiol Neurootol. 2003;8:28–37. doi: 10.1159/000067891. [PubMed] [Cross Ref]
13. Mockett BG, Bo X, Housley GD, Thorne PR, Burnstock G. Autoradiographic labelling of P2 purinoceptors in the guinea-pig cochlea. Hear Res. 1995;84:177–193. doi: 10.1016/0378-5955(95)00024-X. [PubMed] [Cross Ref]
14. Xiang Z, Bo X, Burnstock G. P2X receptor immunoreactivity in the rat cochlea, vestibular ganglion and cochlear nucleus. Hear Res. 1999;128:190–196. doi: 10.1016/S0378-5955(98)00208-1. [PubMed] [Cross Ref]
15. Nikolic P, Housley GD, Luo L, Ryan AF, Thorne PR. Transient expression of P2X(1) receptor subunits of ATP-gated ion channels in the developing rat cochlea. Brain Res Dev Brain Res. 2001;126:173–182. doi: 10.1016/S0165-3806(00)00149-8. [PubMed] [Cross Ref]
16. Salih SG, Housley GD, Raybould NP, Thorne PR. ATP-gated ion channel expression in primary auditory neurones. NeuroReport. 1999;10:2579–2586. doi: 10.1097/00001756-199908200-00026. [PubMed] [Cross Ref]
17. Salih SG, Housley GD, Burton LD, Greenwood D. P2X2 receptor subunit expression in a subpopulation of cochlear type I spiral ganglion neurones. NeuroReport. 1998;9:279–282. doi: 10.1097/00001756-199801260-00019. [PubMed] [Cross Ref]
18. Wang JC, Raybould NP, Luo L, Ryan AF, Cannell MB, Thorne PR, Housley GD. Noise induces up-regulation of P2X2 receptor subunit of ATP-gated ion channels in the rat cochlea. NeuroReport. 2003;14:817–823. doi: 10.1097/00001756-200305060-00008. [PubMed] [Cross Ref]
19. Vlajkovic SM, Thorne PR, Sevigny J, Robson SC, Housley GD. NTPDase1 and NTPDase2 immunolocalization in mouse cochlea: implications for regulation of p2 receptor signaling. J Histochem Cytochem. 2002;50:1435–1442. [PubMed]
20. Vlajkovic SM, Thorne PR, Sevigny J, Robson SC, Housley GD. Distribution of ectonucleoside triphosphate diphosphohydrolases 1 and 2 in rat cochlea. Hear Res. 2002;170:127–138. doi: 10.1016/S0378-5955(02)00460-4. [PubMed] [Cross Ref]
21. Vlajkovic SM, Vinayagamoorthy A, Thorne PR, Robson SC, Wang CJ, Housley GD. Noise-induced up-regulation of NTPDase3 expression in the rat cochlea: implications for auditory transmission and cochlear protection. Brain Res. 2006;1104:55–63. doi: 10.1016/j.brainres.2006.05.094. [PubMed] [Cross Ref]
22. Bobbin RP, Thompson MH. Effects of putative transmitters on afferent cochlear transmission. Ann Otol Rhinol Laryngol. 1978;87:185–190. [PubMed]
23. Kujawa SG, Erostegui C, Fallon M, Crist J, Bobbin RP. Effects of adenosine 5′-triphosphate and related agonists on cochlear function. Hear Res. 1994;76:87–100. doi: 10.1016/0378-5955(94)90091-4. [PubMed] [Cross Ref]
24. Kujawa SG, Fallon M, Bobbin RP. ATP antagonists cibacron blue, basilen blue and suramin alter sound-evoked responses of the cochlea and auditory nerve. Hear Res. 1994;78:181–188. doi: 10.1016/0378-5955(94)90024-8. [PubMed] [Cross Ref]
25. Munoz DJ, Thorne PR, Housley GD, Billett TE, Battersby JM. Extracellular adenosine 5′-triphosphate (ATP) in the endolymphatic compartment influences cochlear function. Hear Res. 1995;90:106–118. doi: 10.1016/0378-5955(95)00152-3. [PubMed] [Cross Ref]
26. Sueta T, Paki B, Everett AW, Robertson D. Purinergic receptors in auditory neurotransmission. Hear Res. 2003;183:97–108. doi: 10.1016/S0378-5955(03)00221-1. [PubMed] [Cross Ref]
27. Thorne PR, Munoz DJ, Housley GD. Purinergic modulation of cochlear partition resistance and its effect on the endocochlear potential in the Guinea pig. J Assoc Res Otolaryngol. 2004;5:58–65. doi: 10.1007/s10162-003-4003-4. [PMC free article] [PubMed] [Cross Ref]
28. Dulon D, Mollard P, Aran JM. Extracellular ATP elevates cytosolic Ca2+ in cochlear inner hair cells. NeuroReport. 1991;2:69–72. doi: 10.1097/00001756-199102000-00001. [PubMed] [Cross Ref]
29. Sugasawa M, Erostegui C, Blanchet C, Dulon D. ATP activates non-selective cation channels and calcium release in inner hair cells of the guinea-pig cochlea. J Physiol. 1996;491(Pt 3):707–718. [PubMed]
30. Raybould NP, Jagger DJ, Housley GD. Positional analysis of guinea pig inner hair cell membrane conductances: implications for regulation of the membrane filter. J Assoc Res Otolaryngol. 2001;2:362–376. doi: 10.1007/s101620010087. [PMC free article] [PubMed] [Cross Ref]
31. Cho H, Harada N, Yamashita T. Extracellular ATP-induced Ca2+ mobilization of type I spiral ganglion cells from the guinea pig cochlea. Acta Otolaryngol. 1997;117:545–552. doi: 10.3109/00016489709113435. [PubMed] [Cross Ref]
32. Salih SG, Jagger DJ, Housley GD. ATP-gated currents in rat primary auditory neurones in situ arise from a heteromultimeric P2X receptor subunit assembly. Neuropharmacology. 2002;42:386–395. doi: 10.1016/S0028-3908(01)00184-8. [PubMed] [Cross Ref]
33. Ito K, Dulon D. Nonselective cation conductance activated by muscarinic and purinergic receptors in rat spiral ganglion neurons. Am J Physiol Cell Physiol. 2002;282:C1121–C1135. [PubMed]
34. Ito K, Rome C, Bouleau Y, Dulon D. Substance P mobilizes intracellular calcium and activates a nonselective cation conductance in rat spiral ganglion neurons. Eur J Neurosci. 2002;16:2095–2102. doi: 10.1046/j.1460-9568.2002.02292.x. [PubMed] [Cross Ref]
35. Shen J, Harada N, Yamashita T. Nitric oxide inhibits adenosine 5′-triphosphate-induced Ca2+ response in inner hair cells of the guinea pig cochlea. Neurosci Lett. 2003;337:135–138. doi: 10.1016/S0304-3940(02)01320-4. [PubMed] [Cross Ref]
36. Shen J, Harada N, Nakazawa H, Yamashita T. Involvement of the nitric oxide-cyclic GMP pathway and neuronal nitric oxide synthase in ATP-induced Ca2+ signalling in cochlear inner hair cells. Eur J Neurosci. 2005;21:2912–2922. doi: 10.1111/j.1460-9568.2005.04135.x. [PubMed] [Cross Ref]
37. Yukawa H, Shen J, Harada N, Cho-Tamaoka H, Yamashita T. Acute effects of glucocorticoids on ATP-induced Ca2+ mobilization and nitric oxide production in cochlear spiral ganglion neurons. Neuroscience. 2005;130:485–496. doi: 10.1016/j.neuroscience.2004.09.037. [PubMed] [Cross Ref]
38. Rennie KJ, Ashmore JF. Effects of extracellular ATP on hair cells isolated from the guinea-pig semicircular canals. Neurosci Lett. 1993;160:185–189. doi: 10.1016/0304-3940(93)90409-E. [PubMed] [Cross Ref]
39. Nagata N, Harada N, Chen L, Cho H, Tomoda K, Yamashita T. Extracellular adenosine 5′-ATP-induced calcium signaling in isolated vestibular ganglion cells of the guinea pig. Acta Otolaryngol. 2000;120:704–709. doi: 10.1080/000164800750000216. [PubMed] [Cross Ref]
40. Ito K, Chihara Y, Iwasaki S, Komuta Y, Sugasawa M, Sahara Y (2010) Functional ligand-gated purinergic receptors (P2X) in rat vestibular ganglion neurons. Hear Res. doi:10.1016/j.heares.2010.03.081 [PubMed]
41. Vlajkovic SM, Abi S, Wang CJ, Housley GD, Thorne PR. Differential distribution of adenosine receptors in rat cochlea. Cell Tissue Res. 2007;328:461–471. doi: 10.1007/s00441-006-0374-2. [PubMed] [Cross Ref]
42. Vlajkovic SM, Lee KH, Wong AC, Guo CX, Gupta R, Housley GD, Thorne PR (2010) Adenosine amine congener mitigates noise-induced cochlear injury. Purinergic Signal (this issue) [PMC free article] [PubMed]
43. Wong AC, Guo CX, Gupta R, Housley GD, Thorne PR, Vlajkovic SM. Post exposure administration of A(1) adenosine receptor agonists attenuates noise-induced hearing loss. Hear Res. 2010;260:81–88. doi: 10.1016/j.heares.2009.12.004. [PubMed] [Cross Ref]
44. Hu BH, Zheng XY, McFadden SL, Kopke RD, Henderson D. R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla. Hear Res. 1997;113:198–206. doi: 10.1016/S0378-5955(97)00143-3. [PubMed] [Cross Ref]
45. Hight NG, McFadden SL, Henderson D, Burkard RF, Nicotera T. Noise-induced hearing loss in chinchillas pre-treated with glutathione monoethyl ester and R-PIA. Hear Res. 2003;179:21–32. doi: 10.1016/S0378-5955(03)00067-4. [PubMed] [Cross Ref]
46. Tritsch NX, Yi E, Gale JE, Glowatzki E, Bergles DE. The origin of spontaneous activity in the developing auditory system. Nature. 2007;450:50–55. doi: 10.1038/nature06233. [PubMed] [Cross Ref]
47. Greenwood D, Jagger DJ, Huang LC, Hoya N, Thorne PR, Wildman SS, King BF, Pak K, Ryan AF, Housley GD. P2X receptor signaling inhibits BDNF-mediated spiral ganglion neuron development in the neonatal rat cochlea. Development. 2007;134:1407–1417. doi: 10.1242/dev.002279. [PubMed] [Cross Ref]
48. Munoz DJ, Thorne PR, Housley GD, Billett TE. Adenosine 5′-triphosphate (ATP) concentrations in the endolymph and perilymph of the guinea-pig cochlea. Hear Res. 1995;90:119–125. doi: 10.1016/0378-5955(95)00153-5. [PubMed] [Cross Ref]
49. Munoz DJ, Kendrick IS, Rassam M, Thorne PR. Vesicular storage of adenosine triphosphate in the guinea-pig cochlear lateral wall and concentrations of ATP in the endolymph during sound exposure and hypoxia. Acta Otolaryngol. 2001;121:10–15. [PubMed]
50. Zhao HB, Yu N, Fleming CR. Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear. Proc Natl Acad Sci U S A. 2005;102:18724–18729. doi: 10.1073/pnas.0506481102. [PubMed] [Cross Ref]
51. Jagger DJ, Housley GD. Membrane properties of type II spiral ganglion neurones identified in a neonatal rat cochlear slice. J Physiol. 2003;552:525–533. doi: 10.1111/j.1469-7793.2003.00525.x. [PubMed] [Cross Ref]
52. Weisz C, Glowatzki E, Fuchs P. The postsynaptic function of type II cochlear afferents. Nature. 2009;461:1126–1129. doi: 10.1038/nature08487. [PMC free article] [PubMed] [Cross Ref]
53. Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem. 2007;76:387–417. doi: 10.1146/annurev.biochem.75.103004.142819. [PubMed] [Cross Ref]
54. Pedersen SF, Owsianik G, Nilius B. TRP channels: an overview. Cell Calcium. 2005;38:233–252. doi: 10.1016/j.ceca.2005.06.028. [PubMed] [Cross Ref]
55. Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature. 2004;432:723–730. doi: 10.1038/nature03066. [PubMed] [Cross Ref]
56. Nagata K, Duggan A, Kumar G, Garcia-Anoveros J. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci. 2005;25:4052–4061. doi: 10.1523/JNEUROSCI.0013-05.2005. [PubMed] [Cross Ref]
57. Balaban CD, Zhou J, Li HS. Type 1 vanilloid receptor expression by mammalian inner ear ganglion cells. Hear Res. 2003;175:165–170. doi: 10.1016/S0378-5955(02)00734-7. [PubMed] [Cross Ref]
58. Ishibashi T, Takumida M, Akagi N, Hirakawa K, Anniko M. Expression of transient receptor potential vanilloid (TRPV) 1, 2, 3, and 4 in mouse inner ear. Acta Otolaryngol. 2008;128:1286–1293. doi: 10.1080/00016480801938958. [PubMed] [Cross Ref]
59. Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear. Acta Otolaryngol. 2009;129:1340–1350. doi: 10.3109/00016480902725254. [PubMed] [Cross Ref]
60. Takumida M, Anniko M. Expression of canonical transient receptor potential channel (TRPC) 1–7 in the mouse inner ear. Acta Otolaryngol. 2009;129:1351–1358. doi: 10.3109/00016480902798350. [PubMed] [Cross Ref]
61. Tadros SF, Kim Y, Phan PA, Birnbaumer L, Housley GD. TRPC3 ion channel subunit immunolocalization in the cochlea. Histochem Cell Biol. 2010;133:137–147. doi: 10.1007/s00418-009-0653-6. [PubMed] [Cross Ref]
62. Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Expression of transient receptor potential channel melastin (TRPM) 1–8 and TRPA1 (ankyrin) in mouse inner ear. Acta Otolaryngol. 2008;129:1050–1060. doi: 10.1080/00016480802570545. [PubMed] [Cross Ref]
63. Takumida M, Anniko M. Expression of transient receptor potential channel mucolipin (TRPML) and polycystine (TRPP) in the mouse inner ear. Acta Otolaryngol. 2010;130:196–203. doi: 10.3109/00016480903013593. [PubMed] [Cross Ref]
64. Bauer CA, Brozoski TJ, Myers KS. Acoustic injury and TRPV1 expression in the cochlear spiral ganglion. Int Tinnitus J. 2007;13:21–28. [PubMed]
65. Kitahara T, Li HS, Balaban CD. Changes in transient receptor potential cation channel superfamily V (TRPV) mRNA expression in the mouse inner ear ganglia after kanamycin challenge. Hear Res. 2005;201:132–144. doi: 10.1016/j.heares.2004.09.007. [PubMed] [Cross Ref]
66. Ishibashi T, Takumida M, Akagi N, Hirakawa K, Anniko M. Changes in transient receptor potential vanilloid (TRPV) 1, 2, 3 and 4 expression in mouse inner ear following gentamicin challenge. Acta Otolaryngol. 2009;129:116–126. doi: 10.1080/00016480802032835. [PubMed] [Cross Ref]
67. Phan PA, Tadros SF, Kim Y, Birnbaumer L, Housley GD. Developmental regulation of TRPC3 ion channel expression in the mouse cochlea. Histochem Cell Biol. 2010;133:437–448. doi: 10.1007/s00418-010-0686-x. [PubMed] [Cross Ref]
68. Lee YM, Kim BJ, Kim HJ, Yang DK, Zhu MH, Lee KP, So I, Kim KW. TRPC5 as a candidate for the nonselective cation channel activated by muscarinic stimulation in murine stomach. Am J Physiol Gastrointest Liver Physiol. 2003;284:G604–G616. [PubMed]
69. Kim JY, Saffen D. Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. J Biol Chem. 2005;280:32035–32047. doi: 10.1074/jbc.M500429200. [PubMed] [Cross Ref]
70. Alvarez J, Coulombe A, Cazorla O, Ugur M, Rauzier JM, Magyar J, Mathieu EL, Boulay G, Souto R, Bideaux P, Salazar G, Rassendren F, Lacampagne A, Fauconnier J, Vassort G. ATP/UTP activate cation-permeable channels with TRPC3/7 properties in rat cardiomyocytes. Am J Physiol Heart Circ Physiol. 2008;295:H21–H28. doi: 10.1152/ajpheart.00135.2008. [PubMed] [Cross Ref]
71. Oh EJ, Gover TD, Cordoba-Rodriguez R, Weinreich D. Substance P evokes cation currents through TRP channels in HEK293 cells. J Neurophysiol. 2003;90:2069–2073. doi: 10.1152/jn.00026.2003. [PubMed] [Cross Ref]
72. Beck B, Zholos A, Sydorenko V, Roudbaraki M, Lehen'kyi V, Bordat P, Prevarskaya N, Skryma R. TRPC7 is a receptor-operated DAG-activated channel in human keratinocytes. J Invest Dermatol. 2006;126:1982–1993. doi: 10.1038/sj.jid.5700352. [PubMed] [Cross Ref]
73. Milenkovic I, Rinke I, Witte M, Dietz B, Rubsamen R. P2 receptor-mediated signaling in spherical bushy cells of the mammalian cochlear nucleus. J Neurophysiol. 2009;102:1821–1833. doi: 10.1152/jn.00186.2009. [PubMed] [Cross Ref]

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