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Review

Purinergic signaling in special senses


Gary D. Housley1, Andreas Bringmann2 and Andreas Reichenbach3
1
Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, Faculty of Medicine,
University of New South Wales, Sydney, NSW 2052, Australia
2
Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstraße 10-14, D-04103 Leipzig,
Germany
3
Paul Flechsig Institute of Brain Research, Faculty of Medicine, University of Leipzig, Jahnallee 59, D-04109 Leipzig, Germany

We consider the impact of purinergic signaling on the tic terminals, and from non-neuronal cells by secretion of
physiology of the special senses of vision, smell, taste vesicles or calcium-independent mechanisms via plasma-
and hearing. Purines (particularly ATP and adenosine) membrane nucleotide-transport proteins, connexin or pan-
act as neurotransmitters, gliotransmitters and paracrine nexin hemichannels, anion channels and other processes
factors in the sensory retina, nasal olfactory epithelium, [2]. Adenosine can be released by nucleoside transporters
taste buds and cochlea. The associated purinergic re- or is formed extracellularly from ATP by ecto-nucleoti-
ceptor signaling underpins the sensory transduction and dases [2]. Degradation of nucleotides by ecto-nucleotidases
information coding in these sense organs. The P2 and P1 also provides rapid termination of purinergic signaling [2].
receptors mediate fast transmission of sensory signals As in the brain, purinergic receptors are abundant in the
and have modulatory roles in the regulation of synaptic tissues of special senses. Here, we aim to critically evaluate
transmitter release, for example in the adaptation to what is presently known (and proposed) about the path-
sensory overstimulation. Purinergic signaling regulates ways and roles of purinergic signaling in the special sense
bidirectional neuron–glia interactions and is involved in organs of vision, olfaction, taste and hearing. These can be
the control of blood supply, extracellular ion homeosta- part of the central nervous system such as the retina or of
sis and the turnover of sensory epithelia by modulating the peripheral nervous system such as the inner ear, the
apoptosis and progenitor proliferation. Purinergic sig- olfactory epithelium and taste buds. Moreover, the charac-
naling is an important player in pathophysiological pro- teristics of the stimulus in addition to the degree of local
cesses in sensory tissues, and has both detrimental (pro- information processing differ greatly among the senses.
apoptotic) and supportive (e.g. initiation of cytoprotec- Joint review of purinergic signaling in these sensory sys-
tive stress-signaling cascades) effects. tems provides an opportunity to consider which roles are
adaptations to specific purposes and which are general
Introduction features of the nervous tissue.
The past two decades were witness to a rapid accumulation
of data showing that purinergic signaling is an essential Vision
and crucial factor throughout the vertebrate nervous sys- In the sensory retina, purines are tonically released in
tem. Purines and pyrimidines acting at purinergic P1 and darkness; the release increases with neuronal activity [3].
P2 receptors are extracellular signaling molecules involved ATP is liberated from neurons in a Ca2+-dependent man-
in nearly every aspect of development, pathophysiology, ner [3,4] and from glial and pigment epithelial cells by
neurotransmission and neuromodulation [1,2]. Adenosine Ca2+-independent mechanisms [5–8]. Adenosine might be
(P1) receptors are subdivided into four subtypes (A1, A2A, released via nucleoside transporters by ganglion and glial
A2B and A3), all of which couple to G proteins. P2 receptors cells [8], and it can be formed enzymatically in the extra-
(recognizing primarily adenine and uracil tri- and dinu- cellular space from ATP [9–11]. Ecto-nucleotidases have
cleotides) comprise two families: ionotropic P2X and G- been localized to both plexiform (synaptic) layers [12–14].
protein-coupled P2Y receptors. P2X receptors (which
represent ATP-gated ion channels) are subdivided into
Neurotransmission and neuromodulation
seven subtypes (P2X1 to P2X7); P2Y receptors comprise
In the retina, photoreceptors, most neurons, glial cells, the
at least eight subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11,
microvasculature and pigment epithelial cells express P1
P2Y12, P2Y13 and P2Y14). These subtypes differ in their
and P2 receptors (Table 1). ATP is likely to contribute to
molecular structure and selectivities to agonists and
fast excitatory neurotransmission by activation of P2X
antagonists [1]. P2X receptors contribute to fast excitatory
receptors and has a potential neuromodulatory role acting
synaptic transmission and also act presynaptically to
at P2Y receptors localized to neuronal and supportive cells
modulate neurotransmitter release, whereas P2Y recep-
(Figure 1; Table 1). However, the role of purines in reg-
tors are involved in neuromodulation and neuron–glia
ulating retinal function is not well determined. Under-
interactions. Adenosine has a key role in the regulation
standing the function of ATP in the retina is also
of tissue oxygenation, neuronal firing, neurotransmitter
complicated by species differences. It has been suggested
release and cytoprotective responses. ATP is released as a
that various P2X receptor subtypes are differentially
cotransmitter via vesicle-mediated exocytosis from synap-
involved in specific circuits within the retina; P2X7 might
Corresponding author: Housley, G.D. (g.housley@unsw.edu.au). preferentially modulate signal transmission in the rod
128 0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.01.001 Available online 18 February 2009
Review Trends in Neurosciences Vol.32 No.3

Table 1. Expression of purinergic receptor subtypes in different cell types of the sensory retinaa
Receptor subtypes Species Localization and functional activity Refs
Photoreceptors
A1, A2 Salamanderb,c Inhibition of L-type Ca2+ currents and glutamate release from rods [21]
A2 Rabbitd and mouse d Inner and outer segments of photoreceptors [140]
A2 Teleosts e Induction of cone elongation in dark; increase in cAMP level [141]
A2A Salamander f Inhibition of opsin mRNA expression in rods at night; increase [142]
in cAMP level
P2X2 Ratf,g Somata and outer segments of photoreceptors [143]
P2X7 Rat and marmosetg,h,i Increase in the amplitude of the ERG a-wave [12,16]
P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j, rabbitf and Inner segments of photoreceptors [144–146]
macaque f
Bipolar cells
A1 Rat c Suppression of NMDA-mediated currents [26]
P2X3, P2X 4, P2X 5 Rat j Not determined [147]
P2Y1, P2Y 2, P2Y 4, P2Y 6 Ratg,h,j Not determined [148,149]
Retinal ganglion cells
A1, A2A, A3 Ratf and mouse k Not determined [150,151]
A1 Ratb,c Inhibition of voltage-dependent Ca2+ channels and of the [9,10,23]
glutamate-induced increase in cytosolic Ca2+; activation of K+ channels;
decrease in the spike activity
A1 Salamander 2 Inhibition of N-type Ca2+ channels [22]
A3 Rat b Inhibition of P2X7-receptor-mediated Ca2+ rise and ganglion cell death [58]
P2X2, P2X3, P2X4, Ratf,g,j Not determined [15,143,152–154]
P2X5, P2X 7
P2X7 Ratb,g Sustained increase in cytosolic Ca2+; activation of L-type Ca2+ channels [57]
and of caspases; cell death
g,j
P2X7 Mouse Not determined [155]
P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j Not determined [145,148]
Amacrine cells
A1 Chickb,e and rabbit e Inhibition of N-type Ca2+ channels and PLC; inhibition of ACh release [4,24,25]
P2X1, P2X2, P2X3, Ratg,h and mouse 6 Not determined [13,15,156,157]
P2X5, P2X7
P2X2 Mouse g Inhibition of ACh release from OFF cholinergic amacrines [17,18]
P2X7 Ratg,h,j Not determined [16,154]
Horizontal cells
P2X7 Monkeyg ratg,h Not determined [16,153]
Interplexiform cells
P2X3 Ratg,h Not determined [13]
Retinal astrocytes and Müller cells
A1 Rat e Inhibition of osmotic cell swelling; activation of K+ and Cl channels [14,31,158]
A1, A2A, A2B Ratb,c Potentiation of light-evoked Ca2+ responses [20]
A2 Rat b Elicitation of Ca2+ waves [159]
P2X7 Humanb,c Ca2+ influx; cell depolarization; activation of BK channels; stimulation [47,160]
of cell proliferation
P2Y1, P2Y2, P2Y4, Salamander b Elicitation of Ca2+ waves [161,162]
P2Y6, P2Y11, P2Y13
P2Y1, P2Y2, P2Y4, P2Y6 Ratb,j Elicitation of Ca2+ responses [8,148,159,164]
P2Y1 Rat e Inhibition of osmotic cell swelling; stimulation of transporter-mediated [8,31]
release of adenosine
P2Y1, P2Y2, P2Y4, P2Y6 Humanb,c,g,j Elicitation of Ca2+ responses; activation of BK channels [163,165]
Retinal microglia
P2X7 Rat e Formation of transmembrane pores; induction of apoptosis; release [166,167]
of inflammatory cytokines (e.g. TNFa, interleukin-1b)
P2Y2, P2Y 4 Rat e Stimulation of cell proliferation [167]
P2Y1 Rabbit e Retraction of cell processes [168]
Pericytes of retinal microvasculature
A1, A2A Rat c Hyperpolarization of pericytes; opening of KATP channels [30]
P2X7, P2Y4 Ratb,c Pericyte depolarization and contraction; Ca2+ responses [169]
P2X7, P2Y4 Ratb,c P2X7: formation of transmembrane pores; activation of [170]
voltage-dependent Ca2+ channels and lethal Ca2+ influx
P2Y4: inhibition of P2X7 pore formation
Retinal pigment epithelium
A1, A 2 Humanb,e Potentiation of ATP-evoked Ca2+ responses [171]
A2 Pig e Increase in cAMP level [172]
A2B Rat e Inhibition of phagocytosis of outer segments; increase in cAMP level [173]
P2X, P2Y Ratb,c P2X: nonselective cation conductance [174]
P2Y: release of Ca2+ from internal stores; activation of BK currents
P2Y1, P2Y2, P2Y4, Humanb,j,l Ca2+ responses [175]
P2Y6, P2Y12
P2Y2 Cowb,c, humanb,c Ca2+-dependent increase in Cl conductance and decrease in K+ [36,37,176]
and rabbite,f conductance; stimulation of the transcellular fluid transport

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Table 1 (Continued )
Receptor subtypes Species Localization and functional activity Refs
Developing retina
A2 Ferret, mouseb,g Increase in the spontaneous activity of ganglion and amacrine cells [177]
by stimulation of adenylyl cyclase and PKA activity
A2A Chick e Increase in the survival of developing retinal neurons; increase [178]
in cAMP level
m
P2Y1 Xenopus Initiation of eye formation; expression of Pax6 and Rx1 [39]
P2Y1 Chick e Stimulation of the proliferation of late progenitors; activation of PLC, [43,44]
PKC and ERKs
P2Y2, P2Y4 Chickb,e Stimulation of the proliferation of early progenitors [7,40,41]
a
Abbreviations: ACh, acetylcholine; BK, Ca2+-activated K+ channels of large conductance; cAMP, cyclic AMP; ERG, electroretinogram; ERK, extracellular signal-regulated
kinase; KATP, ATP-sensitive K+ channels; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.
Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dradioligand labeling; epharmacology; fin-situ hybridization;
g
immunohistochemistry; helectron microscopy; ienzyme histochemistry; jRT–PCR; ktransgene expression; lwestern blotting; mreceptor knockdown.

pathway and P2X2 in the cone pathway [12,15,16]. P2X7 is OFF pathways, with a selective enrichment of P2X2 in
expressed by nearly every type of retinal neuron (Table 1). OFF cholinergic amacrines [17,18]. Here, ATP increases
In the rat retina, P2X7 was localized to photoreceptor g-aminobutyric acid (GABA)ergic inhibitory postsynaptic
terminals near the ribbon synapse, to horizontal cells currents in OFF but not ON cholinergic amacrines, and
invaginating the photoreceptor terminals and to amacrine suppresses OFF ganglion cells but activates ON ganglion
cells that provide synaptic input onto the rod bipolar cells [17]. In the rat retina, P2X2 is localized to GABA-
terminal [12,16]. P2X7 receptor activation results in an ergic amacrine cells (that form synapses with cone but
increase of the photoreceptor-derived a-wave of the elec- not rod bipolars) and a population of ganglion cells [15]. A
troretinogram and in transient reduction of the photo- further unresolved problem is the source(s) of ATP
receptor-derived postsynaptic responses [15]. involved in synaptic transmission. It has been speculated
In the mouse retina, ATP might modulate signal pro- that ATP is co-released with GABA from GABAergic
cessing of the ON and OFF pathways in an asymmetrical amacrines and horizontal cells [16], with acetylcholine
manner. The immunohistochemical distribution of dis- from cholinergic amacrines [19] and, possibly, from
tinct P2X receptor subtypes differs between the ON and ganglion cells [20].

Figure 1. Purinergic signaling in the retina. The following purinergic paths are symbolized by the arrows: (1) modulation of processes of transduction in the photoreceptor
cells; this involves A1 and A2 receptors and several types of P2X and P2Y receptors; the probable agonist sources are glial and/or RPE cells; (2) modulation of signal
processing in the OPL; this involves A1, A2 and P2X7 receptors; the agonist source(s) is unknown; (3) modulation of signal processing in the IPL; this involves A1 and several
types of P2X receptors; the agonist source(s) is unknown; (30 ) modulation of cholinergic amacrine cells; this involves A1 and P2X2 receptors; the signaling source(s) is
unknown; (4) neuron-to-glia signaling; this involves A1, A2 and several P2Y receptor subtypes; the probable source of agonists are ganglion and amacrine cells; (5) autocrine
signaling in Müller glial cells (e.g. for volume regulation); this involves P2Y1 and A1 receptors; (6) glia-to-glia signaling (e.g. Ca2+ waves) of astrocytes and Müller cells; this
involves P2Y receptors; (60 ) signaling (e.g. Ca2+ waves) between RPE cells; (7) glia-to-neuron signaling, arising from Müller cells; this involves A1 receptors and not yet
specified P2X receptors; (8) glia-to-blood vessel signaling (control of blood flow), arising from astrocytes and Müller cells; (9) control of RPE functions including water
clearance from subretinal space; this involves P2Y2 receptors; the agonist source(s) is unknown; and (10) control of progenitor and Müller cell proliferation; this involves
several types of P2Y receptors (and, in culture, P2X7 receptors); the agonist source(s) is unknown. Abbreviations: A, amacrine cells; AS, astrocyte; B, bipolar cells; BV, blood
vessel; C, cone photoreceptor cell; G, retinal ganglion cells; GCL, ganglion cell layer; H, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer; M, Müller cell;
OFF, sublayer of the IPL where light-off information is processed; ON, sublayer of the IPL where light-on information is processed; ONL, outer nuclear layer; OPL, outer
plexiform layer; PRS, photoreceptors segments; R, rod photoreceptor cell; RPE, retinal pigment epithelium.

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Adenosine suppresses excitatory neurotransmission in stimulates the proliferation of early retinal progenitors
the retina by various mechanisms (Table 1) including (by activation of P2Y2 and/or P2Y4 receptors) [7,40,41]
inhibition of presynaptic voltage-dependent calcium chan- and of late glial and bipolar progenitors (by P2Y1 receptors)
nels resulting in reduced transmitter release, for example [42–44]. The division of progenitor cells in the ventricular
of glutamate [21–23], acetylcholine [4,18,24,25] and ATP zone of the chick retina is likely to be stimulated by ATP
[4]. Adenosine inhibits the activity of N-methyl-D-aspar- released from the pigment epithelium [7,45].
tate (NMDA) receptors [23,26] and phospholipase C [25],
and increases the activity of GABAA receptor channels [27] Retinal pathophysiology
and KATP (ATP-sensitive K+) channels [28]. Cellular proliferation is a common response of retinal glial
cells to pathogenic stimuli involved in the formation of glial
Neuron–glia signaling and supportive functions scars [46]. Glial cell proliferation is stimulated by ATP
Purinergic signaling might be implicated in the bidirec- [47,48]; a bidirectional interaction between P2Y and
tional dialogue between neurons and glial cells in the growth factor receptors seems to be involved in this effect.
retina. Flickering light was shown to increase the fre- The mitogenic effect of ATP depends on a release of growth
quency of Ca2+ transients in glial cells, which is likely to factors and on transactivation of growth factor receptor
be mediated by ATP released from neurons and sub- tyrosine kinases [49], whereas growth factors trigger a
sequent activation of P2Y receptors [20]. The purinergic rapid resensitization of P2Y receptors, which are desensi-
neuron-to-glia signaling might trigger an activation of glial tized by ATP [50]. However, the involvement of these
cells implicated in the light-evoked dilation and constric- mechanisms in retina injuries in situ remains to be deter-
tion of retinal arterioles (neurovascular coupling) [29]. mined. Retinal gliosis in situ is characterized by an early
Adenosine increases the retinal blood flow through relaxa- increase in P2-receptor-mediated Ca2+ responses
tion of pericytes [30]; a contribution of glia-derived adeno- [47,51,52] indicating that ATP is one signal that initiates
sine, released in response to glutamate [8,31], remains to retina protection and repair.
be confirmed. Excess ATP, released in response to pathogenic factors
Purines released from retinal glial cells were suggested such as mechanical perturbations [5,9] and elevated intra-
to modulate synaptic activity [9]. Activation of glial cells, ocular pressure [53–55], might be also implicated in
for example by glutamate or electrical and mechanical neuronal degeneration. P2X receptors are highly Ca2+
stimulation, triggers intercellular Ca2+ waves in the glial permeable [56]. Prolonged activation of P2X7 receptors
network [32,33]. The propagation of the waves depends induces retinal ganglion cell death via Ca2+-dependent
upon the release of ATP and activation of P2Y receptors mechanisms [57]. ATP-evoked ganglion cell death could
[5,32] and is associated with an alteration in the light- be involved in glaucoma [53]. The balance between extra-
evoked activity of ganglion cells [33]. ATP released from cellular ATP and adenosine levels might determine the
activated glial cells into the inner plexiform layer [5,9] level of ganglion cell death because adenosine inhibits the
might be converted extracellularly to adenosine that acti- P2X7-receptor-mediated Ca2+ rise and apoptosis of
vates A1 receptors in a population of ganglion cells, result- ganglion cells [58]. However, whether ATP would be
ing in a depression of spontaneous activity [9,10]. released in levels high enough to overcome rapid conver-
Purines also regulate supportive functions of retinal glial sion to adenosine is not known. A rapid release of adeno-
and pigment epithelial cells. Glutamatergic neurotrans- sine is an important component of the retinal response to
mission in the retina is associated with changes in cellular ischemia or hypoxia [11,59]. Adenosine induces retinal
and extracellular volume [31,34] and with a decrease in the hyperemia after ischemia [60] and might protect neurons
osmolarity of the extracellular fluid [35]. Retinal glial cells from glutamate toxicity by suppression of excitatory neuro-
possess a purinergic signaling mechanism that maintains transmission. Activation of A1 and/or A2 receptors, or
their volume constant, to prevent a detrimental shrinkage of ischemic preconditioning mediated by endogenous adeno-
the extracellular space under hypo-osmotic conditions [34]. sine and A1 receptor activation, protects the retina from
This mechanism involves the release of ATP and adenosine ischemic injury [28,61,62].
and the autocrine activation of P2Y1 and A1 receptors [8,31]
and can be triggered by glutamate derived from neurons or Olfaction
glial cells [31,34]. Activation of P2Y1, P2Y2 and A1 receptors The nose of vertebrates utilizes various systems for che-
stimulates the absorption of excess fluid from the retinal mosensation including the main olfactory system, vomer-
tissue across the pigment epithelium [36,37] and, probably, onasal organ, Grüneberg ganglion and trigeminal system.
by glial cells [38]. This is required to redistribute metabo- The main olfactory epithelium consists of olfactory recep-
lically generated water (to prevent edema formation) and to tor neurons, glia-like sustentacular cells, microvillar cells
maintain a proper attachment of the neuroretina to the and basal cells. Here, extracellular ATP might be released
pigment epithelium. from receptor neurons and their axons [63,64], from sym-
pathetic and trigeminal nerve fibers [65–67] and from cells
Retinal development that are acutely injured by toxic compounds, for example
Purinergic signaling is involved in the early eye formation highly concentrated odorants [68]. It has been suggested
and retinal development. In Xenopus laevis, ADP, extra- that there is a constant low level of extracellular ATP in the
cellularly formed from ATP, triggers the expression of the main olfactory epithelium that induces a tonic suppression
eye field transcription factors Pax6 and Rx1, which are of the activity of receptor neurons [69] and trigeminal
necessary for eye development [39]. In the chick, ATP fibers [63].

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


junctions, thus enhancing the functional coupling between
the cells [73]. ATP released from injured cells could initiate
protective responses such as (i) reduction of the odorant
sensitivity of receptor neurons [69], (ii) induction of heat-
shock proteins in sustentacular cells, which might facili-
tate inhalant detoxification [68] and (iii) stimulation of
basal cell proliferation to regenerate the damaged tissue
[69]. Chemosensory trigeminal neurons express P2X2
receptors; the suppression of P2X2 receptor currents by
distinct odorants might contribute to central odor recog-
nition [63]. In the vomeronasal organ, primary olfactory
neurons and secretory cells express purinergic receptors
[74].

Taste
Multiple purinergic signaling pathways contribute to the
coding and transmission of taste sensation, particularly for
taste buds, which occur on the tongue (lingual), palate and
larynx [75] (Figure 3; Table 3). In the taste bud, ATP is
released as a neurotransmitter and as a paracrine signal
for coupling taste cells with differing transduction modal-
ities and glia–sensory-cell communication. This occurs via
a non-vesicular mechanism involving pannexin 1 [76] and
connexin [77] hemichannels. Chemosensory cells and
fibers in the oral cavity and upper alimentary tract also
contribute to taste and broader chemosensory transduc-
Figure 2. Purinergic signaling in the olfactory epithelium. The following purinergic
paths are symbolized by the arrows: (1 and 10 ) modulation of signal integration tion, but with limited modality and less compelling evi-
and/or firing rate; this involves several types of P2X and P2Y2 receptors; the dence for purinergic signaling.
agonist source(s) might be other ORNs and/or efferent nerves; a possible
purinergic glia-to-neuron signaling remains to be determined; (2) neuron-to-glia
ATP release from taste-bud type II receptor cells (TR-
signaling might involve several types of P2X and P2Y1 and P2Y2 receptors; the expressing cells) is central to the coding of sweet, bitter and
agonist source(s) is probably ORNs; (3) glia-to-glia signaling among the umami taste, acting directly on P2X2 and P2X3 hetero-
sustentacular cells (Ca2+-wave-induced modification of gap-junctional coupling);
and (4) control of progenitor cell proliferation; this involves P2X1 and P2Y2
meric receptors at the chemosensory afferent terminals
receptors; the agonist source(s) might be ORNs and/or SCs. Abbreviations: BC, [75] of the chorda tympani branch of the facial nerve (n.
basal cell; DK, dendritic knob; ORN, olfactory receptor neuron; SC, sustentacular VII) and in the posterior aspect of tongue via glossophar-
cell; TB, tubular bone.
yngeal (n. IX) innervation. The sweet modality utilizes the
T1R2–T1R3 receptor dimer, with bitter tastes transduced
In the main olfactory epithelium, ATP could activate via a large family of T2R receptors and umani (the ‘meati-
multiple P2 receptor subtypes expressed by receptor ness’ of monosodium glutamate) attributed to an N-term-
neurons, sustentacular cells, basal cells (Figure 2; inal variant of the metabotropic glutamate mGlu4 receptor
Table 2), solitary microvillar cells [70] and trigeminal and the T1R1–T1R3 receptor dimer; these are all G-protein
nerve fibers. Activation of P2X and P2Y receptors in mur- coupled (for review, see Ref. [78]). In a P2X2/P2X3 double
ine olfactory receptor neurons evokes inward currents and knockout mouse model, all gustatory transmission was lost
cytosolic Ca2+ responses and reduces the odorant-induced from lingual taste buds [75]. Although the type II taste-bud
activity of the cells [69]; this indicates that P2 receptors TR-expressing cells do not possess synaptic proteins,
modulate odor sensitivity implicated, for example, in odor recent transgenic mouse studies using T1R3 promoter/
adaptation. P1 and P2 receptors might also be involved in enhancer-driven wheat germ aglutinin expression con-
olfactory receptor trafficking [71]. In sustentacular cells, firmed the intimate coupling of the sweet and umami type

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


Receptor subtypes Species Localization and functional activity Refs
Olfactory receptor neurons
P2X1, P2X4, P2Y2 Mouseb,d Elicitation of inward currents and Ca2+ responses; reduction in odor sensitivity [69]
P2X3, P2X5, P2X7 Rat d Not determined [74]
Sustentacular supporting cells
P2X5, P2X7, P2Y1 Rat d Not determined [74]
P2Y Mouseb,c Elicitation of Ca2+ responses; activation of BK channels; opening of gap junctions [69,73]
P2Y2, P2Y4 Moused, Xenopus b Elicitation of Ca2+ responses [69,72]
Basal cells
P2X1, P2Y2 Mouse d Not determined [69]
P2X7 Rat d Not determined [74]
a
Abbreviations: BK, Ca2+-activated K+ channels of large conductance.
Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dimmunohistochemistry.

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pholipase C (PLC)b2–Ins(1,4,5)P3 [inositol (1,4,5)-trispho-


sphate]-receptor-3-gated Ca2+-store pathway. Several G-
protein heterotrimers are implicated in taste transduction
and add breadth to the response characteristics, whereas
transduction of the other two modalities (i.e. sour and
salty) involves additional transduction pathways [78].
The most notable markers of the taste-bud receptor cells
are the T1Rs, T2Rs, the bitter tastant G protein a gustdu-
cin, sweet tastant Ga14 [81], PLCb2 and the Ca2+-gated
transient receptor potential channel TRPM5. The Ca2+
signal for triggering ATP release is likely to include the
TRPM5 channel and voltage-gated Na+ channels [77];
concurrent elevation of cytosolic Ca2+ and membrane
depolarization activate Px1 [82]. Encoding of tastant
responses might reflect the generator potential activity
of the receptor cells. Although receptor cells do not express
G-protein-coupled receptors for different tastant modal-
ities, there will be multi-modal integration of the tastant
responses at the chemoreceptor afferents because the same
fiber innervates multiple receptor cells [78] and the TR-
expressing cells and type III (presynaptic) taste cells are
coupled via P2X- and P2Y-receptor-mediated paracrine
signaling.
In addition to the direct coupling of the taste-bud TR-
expressing (type II) cells to a subset of purinergic intragem-
mal fibers, paracrine ATP signaling to the adjacent presyn-
aptic cells is likely to modulate the serotonergic
transmission at these conventional synapses via activation
of P2X and P2Y receptors. Ca2+ entry and release of Ca2+
from Ins(1,4,5)P3-gated stores provides a stimulus that
drives exocytosis of serotonin-containing synaptic vesicles
Figure 3. Schematic summary of purinergic signaling in the taste bud. The following [76,78]. Serotonin might then activate chemoreceptor affer-
purinergic paths are symbolized by the arrows: ATP is released from the (type II)
ents (as yet unconfirmed), and additional local release of
taste-bud receptor cells via pannexin 1 (and connexin) hemichannels and (1) acts as a
neurotransmitter directly on the nerve endings of purinergic chemosensory afferent serotonin might itself have paracrine action within the taste
fibers (via P2X2 and P2X3 receptors) to encode sweet, bitter and umami tastants; (2) bud via serotonin 5-HT1 receptors [78,83]. The presynaptic
released ATP also has an autocrine and paracrine action on the receptor cells and
provides a coupling signal to the presynaptic (type III) taste-bud cells that release
cells directly transduce tastants. For example, each taste
serotonin as a neurotransmitter and neuromodulator (these are predominantly sour- bud contains several of these cells that express the putative
sensing cells); this is mediated by activation of P2X2 and P2Y1 receptors to produce a sour-sensing TRP channel PKD2L1 [84]. Analysis of P2X
Ca2+ signal; (3) ATP autocrine action via P2Y1, P2Y2 and P2Y4 receptors to regulate
ATP release; (4) the enshrouding glial (type I) cells signal to the type IV cells, which
and P2Y expression highlights the functional coupling be-
stimulate these precursor cells to sustain the replacement of the high turnover of tween all types of taste receptor cells. Given that each
taste receptor cells; and (5) high levels of NTPDase2 on the cell surface of the type I mammalian taste bud contains 80 cells, ATP will diffuse
cells terminate the ATP signal.
to adjacent receptor, synaptic and glial (type I) cells, in
addition to the precursor (type IV) cells, activating the full
II receptor cells to the P2X-receptor-expressing intragem- range of these purinergic receptors, depending upon agonist
mal nerve fibers of the taste buds [79,80]; this is indicative type (e.g. ATP versus ADP) and concentration.
of direct purinergic transmission, albeit with unconven- It is notable that functional P2X7 receptor expression
tional synaptic connectivity. has been identified in the mouse fungiform taste-bud cells,
P2Y receptors probably modulate ATP (transmitter) implicating this pathway in the apoptotic mechanisms
release via autocrine and paracrine feedback via the phos- associated with their rapid turnover [85]. These are prob-

Table 3. Expression of purinergic signaling elements in taste


Receptor subtypes Species Localization and functional activity Refs
Chorda tympani branch of VII glossopharyngeal n. IX superior laryngeal n. X taste-bud innervation
P2X1, P2X2, P2X3 Rat e Chemosensory (taste) afferent [179,180]
e,g
P2X2–P2X3 heteromer Mouse Chemosensory (taste) afferent [75]
Bud cells
Fungiform, circumvallate and foliate papillae
P2X2, P2X7 Mousea,b,c,e,f P2X2 on presynaptic cells fungiform papilla; P2X7 cell subtype not specified [85]
P2Y1 Rata,d,e,f Expressed in a subset of taste receptor and presynaptic cells; Ca2+ increase with ATP [181]
e,f
P2Y1, P2Y2, P2Y4, P2Y6 Mouse Four dominant P2Y receptors; equally co-expressed in 75% of circumvallate and foliate [85,182]
papillae taste-bud cells; Ca2+ responses
Expression of purinergic receptors was identified by the following methods: aCa2+ imaging; belectrophysiology; cpharmacology; din-situ hybridization; eimmunohistochem-
istry; fRT-PCR; greceptor knockout.

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ably presynaptic cells based on negative results (no change with P2X receptor agonists and antagonists suppresses and
in current) of the P2X7-selective agonist BzATP with voltage enhances, respectively, the compound action potential
clamp of receptor cells from circumvallate taste buds [77]. [90,91], supporting a role for regulation of primary afferent
ATP signaling within the lingual, palatal and laryngeal neurite excitability [91]. In the adult rat and guinea-pig
taste buds is terminated by an ATP-selective ecto-nucleoti- spiral ganglion neurons, the predominant P2X receptors are
dase. An initial histochemical characterization of Ca2+-de- P2X2 and P2X7. Agonists of P2X2, but not P2X7, have a direct
pendent ecto-ATPase activity in taste buds from the golden action on individual afferent auditory fibers affecting the
hamster showed strong labeling of the glial cells that breadth of the tuning curve [92]. P2X2 has been localized to
ensheath the receptor and presynaptic cells [86]. Gene the postsynaptic specializations at the spiral ganglion
transcript screening of taste-bud-enriched tissue, enzyme neuron neurite–hair-cell synapses at both inner and outer
activity assays and immunocytochemistry in mouse sub- hair cells [93], and both type I and type II spiral ganglion
sequently identified this principally as nucleoside tripho- neurons exhibit ATP-gated inward currents at the cell soma
sphate diphosphohydrolase-2 (NTPDase2), which is highly [94]. Glucocorticoids enhance the P2X receptor signaling
selective for ATP over ADP [87]. Thus, ATP signaling is and elicit nitric oxide production by the cells, which provides
tightly constrained within the taste bud and unlikely to spill local signaling [95], potentially interacting with the satellite
over to activate purinergic sensory fibers for touch, tempera- glial cells. P2Y receptor activation in the soma of the spiral
ture and pain [88]. ganglion neurons elicits Ca2+ signaling [96], which recruits a
substantial nonselective cation conductance, impacting on
Hearing primary afferent excitability [97]. The outer hair cells are
The cochlea exhibits a diverse array of purinergic signaling also innervated by cholinergic (olivocochlear) efferent fibers
components. This includes all seven ionotropic P2X receptor that act to reduce hearing sensitivity by modulating outer
subunits and all studied metabotropic P2Y receptors, in hair cell-mediated reverse transduction. P2X7 receptor
addition to P1 receptor signaling via adenosine arising, in expression occurs presynaptically [98] and might influence
part, from conversion of nucleotides by ecto-nucleotidases. this neural feedback.
Figure 4 and Table 4 highlight important purinergic sig-
naling mechanisms supporting the maintenance of sound Paracrine signaling supports cochlear homeostasis
transduction and neurotransmission in the cochlea. In the rodent cochlea, both P2X and P2Y receptors are
extensively expressed in the cochlear partition, and via
Purinergic modulation of auditory neurotransmission autocrine and paracrine action they are likely to reduce the
A role for extracellular ATP as an effector of cochlear driving force for sound transduction when stressors such as
neurotransmission was identified earlier than glutamate acoustic overstimulation or ischemia cause the release of
[89]. Perfusion of the scala tympani (i.e. into the perilymph) ATP into the scala media. P2X2 receptors, in particular, are

Figure 4. Schematic summary of purinergic signaling in the cochlea. The following purinergic paths are symbolized by the arrows: (1) ATP in marginal cells is contained in
vesicles and provides autocrine and paracrine action to inhibit K+ influx into the scala media by a P2Y4 receptor–PLC PKC pathway closing KCNE1/KCNQ1 K+ channels; this
acts in synergy with pathway (5); (2) internal K+-transport regulation within the stria vascularis; this is via the P2Y4 receptor; (3) strial blood vessels; A2A-receptor-mediated
vasodilatation with ischemia; (4) regulation of K+ recycling between perilymph and endolymph via Ca2+ signaling and connexins in the spiral limbus and spiral ligament;
this is via A1, P2X2 and P2Y receptors; (5) K+ shunt out of the endolymph via ATP-gated nonselective channels (which decreases the EP and depolarizes hair cells) works in
synergy with pathway (1); this is mediated by the P2X2 receptor; (6) autocrine action: multiple signaling pathways within the hair cells and adjacent supporting cells affect
the membrane potential and micromechanics of the hair cells and supporting cells, Ca2+ and nitric oxide signaling; this is via P2X2 and P2X7, and P2Y2 and P2Y4 receptors;
(7) paracellular epithelial ion homeostasis in inner and outer sulcus (connexin and pannexin 1 hemichannels); Ca2+ waves and K+ re-absorption during acoustic
overstimulation; this is via P2X2 and P2Y4 receptors; (8) postsynaptic actions at the afferent (spiral ganglion) neurites and terminals at the hair cells (neuromodulation);
during synaptic consolidation before hearing onset, activity to inhibit neurite extension by blocking Trk signaling of neurotrophins; this is via P2X2 and P2X2/P2X3 receptors;
(9) spiral ganglion neuron–neuron or satellite cell (glia)-to-neuron signaling; Ca2+ signaling activates BK channels, regulating spontaneous activity; via A1, A2A and A3, P2X2
and P2X7 receptors (P2X1 and P2X3 during development) and the P2Y receptor; and (10) efferent fiber–hair cell presynaptic regulation of cholinergic efferent inhibition of
outer hair-cell electromotility; this is via the P2X7 receptor. Abbreviations: BM, basilar membrane; BV, blood vessel; DC, Deiters’ cell; HC, Hensen’s cell; IDC, interdental cells;
IHC, inner hair cell; IS, inner sulcus; ISP, inner spiral plexus; OHC, outer hair cell; RM, Reissner’s membrane; SGN, spiral ganglion neuron; ScM, scala media; ScT, scala
tympani; ScV, scala vestibuli; SLG, spiral ligament; SP, spiral prominence; SV, stria vascularis; TM, tectorial membrane.

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Table 4. Expression of purinergic signaling elements in the cochleaa


Receptor subtypes Species Localization and functional activity Refs
Reissner’s membrane
Epithelial cells
P2X1, P2X2 Rate,f Transient downregulated by P10 [183]
P2X2 Rat e K+ shunt from endolymph, protection against acoustic overstimulation [184]
P2X2 Guinea-pigc,f,h K+ shunt from endolymph, protection against acoustic overstimulation [185]
P2X2 Mouse i K+ shunt from endolymph, protection against acoustic overstimulation Housley, G.D.
et al. (abstract) j
Stria vascularis: marginal, intermediate and basal cells
P2Y2, P2Y4 Gerbil, ratc,f P2Y4 on apical surface inhibits KCNE1/KCNQ1 K+ channel via PKC; protection [108,186]
against acoustic overstimulation
Endothelial cells of the strial blood vessels
A2A, A3 Rat f Vasodilatation [135]
Spiral ligament (fibrocytes)
A2A, A3 Rat f Ion recycling [135]
P2X2 Rate,f Ion recycling [100,184]
Outer sulcus epithelial cells (Bottcher’s and Claudius’ cells)
P2X2 Rate,f Paracellular ion recycling [100,184]
P2X2 Mouse f Ion homeostasis [187]
P2X2 Gerbil c Activates nonselective cation channels to shunt K+ from endolymph [188]
P2Y4 Rat c Ion homeostasis [189]
Organ of Corti
Inner and outer hair cells
P2X2 Guinea-pigc,f,g Functionally localized to the apical surface; protection against acoustic [93,110,112]
overstimulation
P2X2 Rate,f K+ shunt, cell deploarization and micromechanics [99,100,113,184]
f
P2X2 Mouse K+ shunt, cell deploarization and micromechanics [187]
P2X7 Rat f Function unknown [98]
P2Y1, P2Y2, P2Y4 Guinea-pigb,c,f PLC; Ins(1,4,5)P3; Ca2+ signaling affects transduction [114,115]
A1, A2A, A3 Rat f Anti-oxidant stress response [135]
Supporting cells (Deiter’s cell, Hensens’ cells, pillar cells, inner phalangeal cells)
A1, A2A, A3 Rat f Otoprotective against ROS [135]
P2 Guinea-pig c Regulates micromechanics [118]
P2X2 Rate,f Micromechanics [100,184]
P2X2 Mouse f Micromechanics [187]
P2X7 Rat f Micromechanics [98]
P2Y Rat PLC; Ins(1,4,5)P3; injury signal through JNK; ERK1/2 signaling
P2Y4 Guinea-pig f Might indicate paracrine ATP release and Ca2+ signaling [190]
Inner sulcus
P2X2 Rate,f Affects K+ shunt and ion homeostasis [100,184]
Interdental cells of the spiral limbus
P2X2 Rate,f Possible role in ion homeostasis [100,184]
Spiral limbus fibrocytes
P2X1 Rate,f Transient down-regulated by P10 [183]
P2X2 Rate,f Ion homeostasis [100,184]
Spiral ganglion neurons
A1, A2A, A3 Rat f Protection from ROS [135]
P2X1, P2X2, P2X3, P2X4, Ratc,d,f,h P2X2 and P2X7 sustained; P2X2/P2X3 early postnatal [98,99,122,125,
P2X5, P2X6, P2X7 183,191–193]
P2Y Guinea-pig d PLC; Ins(1,4,5)P3 [96,192]
P2Y Rat c Regulates neuron excitability [97]
Olivocochlear efferent fibers (bundle)
P2X1 Rate,f Transient downregulation by P10 [183]
P2X7 Rat f Presynaptic; regulates ACh release [98]
Mesenchymal cells
P2X1 Rate,f Transiently expressed during development; downregulated by P10 [183]
a
Abbreviations: Ach, acetylcholine; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; P10, postnatal day 10; PKC, protein kinase C; PLC, phospholipase
C; ROS, reactive oxygen species.
Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dradioligand labeling; ein-situ hybridization; fimmunohis-
tochemistry; gelectron microscopy; hRT–PCR; ireceptor knockout.
j
Housley, G.D. et al. (2008) ATP-mediated humoral inhibition of sound transduction supplants neural efferent inhibition at high sound levels as the mechanism for expanding
the dynamic range of hearing [abstract]. Assoc. Res. Otolaryngol. Abstract 623 (www.aro.org/archives/2008/2008_623_bf2a42ab.html).

highly expressed on the apical surfaces of the cells facing adjacent stria vascularis has a K+ transporter system that
the endolymphatic compartment. This includes Reissner’s generates the endocochlear potential (EP; +100 mV). The
membrane (a two-cell-thick resistive barrier between the EP provides the majority of the driving force for sound
scala media and scala vestibuli), in addition to the inner transduction [101]. Physiological experiments and bio-
and outer sulcus regions and hair cells of the organ of Corti chemical analysis has shown that the ionotropic and meta-
[93,99,100]. All these cells have tight junctions that main- botropic signaling pathways act in synergy to regulate
tain the integrity of the endolymphatic compartment. The electrochemical homeostasis. ATP released into this com-

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partment during the stress of noise or hypoxia, including inner and outer hair cells. This is followed by programmed
release from vesiculated stores in the stria vascularis pruning of mis-matched fibers, with the type I spiral
[102,103] and release from the organ of Corti [104], would ganglion neurons withdrawing from the outer hair cells
activate the P2X2 receptors and produce a shunt conduc- and the type II fibers withdrawing from the inner hair
tance. This shunt has been demonstrated as a reduction cells. This neural re-organization occurs within a few days
in the cochlear partition resistance in the guinea-pig after birth in rodents, just before the onset of hearing. The
when ATP is injected into the endolymph [105]. This outgrowth and branching of the spiral ganglion neurites is
causes a reversible reduction in EP. The ATP signal is supported by neurotrophins secreted by the hair cells,
terminated by ecto-nucleotidase activity [106]. Comple- particularly brain-derived neurotrophic factor (BDNF)
menting this P2X-receptor-mediated shunt of K+ (and and neurotrophin 3 via TrkB and TrkC receptor tyrosine
other minor cations) out of the scala media, the electro- kinase signaling, respectively [121]. P2X receptor sig-
chemical driving force for sound transduction is also naling contributes to the uncoupling of this neurotrophic
decreased by P2Y4 receptor–PLC–protein kinase C support. This is mediated by the transient expression of a
(PKC)-mediated inhibition of the KCNE1/KCNQ1 chan- novel P2X2–P2X3 heteromeric receptor, incorporating an
nels, which provide the K+-influx pathway from the stria uncommon (P2X2-3) splice variant [122–125] that exhibits
vascularis [107,108]. nanomolar ATP sensitivity. Activation of this receptor
Outer hair cells have a key role in sound transduction via blocks the BDNF-dependent outgrowth of the neurites
their electromotility, a unique property that enhances hear- [125].
ing sensitivity and frequency selectivity [109]. Extracellular Extracellular nucleotide signaling also underlies the
ATP acts at nanomolar levels [110] to affect the non-linear induction of neurotransmission in the newly established
capacitance of the electromotility via P2Y receptor sig- innervation of the inner hair cells. Paracrine ATP sig-
naling. At micromolar ATP levels, P2X2-receptor-gated naling is central to this process. The neonatal cochlea is
inward current would alter the electromotility by depolar- structurally distinct in having a transient epithelium (the
izing the cells and by osmotically induced changes in cell Kőlliker’s organ) medial to the inner hair cells. The Kőlli-
volume [111]. The hair-cell P2X-receptor-mediated shunt is ker’s organ epithelial cells spontaneously secrete ATP in
adaptive to noise stress. Very high densities of P2X2 recep- rhythmical bursts that activate P2 receptors on the inner
tors are present on the stereocilia and cuticular plates of the hair cells [126]. This, in turn, elicits synchronized release of
hair cells, but not the basolateral surface [93,112]. In the rat neurotransmitter from the inner hair cells, which activates
model, after 72 h of 90 dB broadband noise, the ATP-gated the type I spiral ganglion neurons. The effect involves ATP-
inward current in outer hair cells increased more than induced ATP release and can be blocked by treating the
threefold, which correlated with enhanced P2X2 immuno- tissue with apyrase, which hydrolyses endogenous ATP.
labelling on the stereocilia [113]. There was also an upre- The purinergic receptors involved in this process, and the
gulation in P2X2 transcript expression in the surrounding pathway for release of ATP, have not been characterized at
cochlear partition epithelium, detected at 6 hours of sus- a molecular level but involve both P2X and P2Y receptors
tained noise exposure onwards. causing ATP release via connexin hemichannels in Kőlli-
Sound transduction in outer hair cells might also be ker’s organ. ATP diffuses to the inner hair cells, where
affected by P2Y-receptor-mediated Ca2+ signaling. P2Y2 inward currents, consistent with activation of P2X recep-
immunolabeling localizes to the apical region of the tors, lead to Ca2+ influx and pulsatile release of glutamate
guinea-pig outer hair cells [114]. Hensen’s body, an at the ribbon synapses with the spiral ganglion neurites.
Ins(1,4,5)P3-receptor-gated Ca2+ store under the cuticular Rhythmic firing in the cochlear nerve ceases around the
plate, is activated by this P2Y receptor signaling via liber- time that the auditory canal opens in rodents (P11), and
ation of a G protein in the hair bundle, and the localized sound-conduction-induced activity commences. This ATP-
elevation in Ca2+ probably alters actin binding, affecting mediated activation of cochlear primary-afferent firing is
stereocilia stiffness [115]. P2-receptor-mediated Ca2+ sig- associated with the maturation of the central auditory
naling within Deiters’ cells, originating in the apical pha- pathways, particularly the cochlear nuclei, and probably
langeal process that projects to the reticular lamina between consolidates the central synaptic mapping of cochlear
the outer hair-cell cuticular plates, causes changes in the tonotopy [127].
stiffness of the cells that would affect transduction [116–
118]. Cochlear pathophysiology
Overall, purinergic signaling in the cochlear partition ATP release in the supporting cells of the organ of Corti
can be viewed as a protective adaptation mechanism. As and spiral ligament is mediated via connexin [110] and
the sound level rises, elevation of ATP from a low nano- probably also pannexin 1 hemichannels [128]. Gap junc-
molar concentration [103,119] would activate the puriner- tions, particularly heteromers of Cx26 and Cx30, form the
gic signaling pathways, desensitize the transduction and conduit for ionic recirculation between the perilymph and
transmission processes and thereby extend the safe range endolymph in response to the standing flux through the
for hearing from the level where the neural efferent inhi- hair cells [129,130]. Disruption of this conduit leads to
bition of the outer hair cells saturates [120]. pathological changes in structure and function, which
might arise, in part, from the block of purinergic signaling.
Cochlear development Ca2+ signaling between gap-junction-coupled cells
During development, both type I and type II spiral involves Cx and Px hemichannel-mediated ATP release,
ganglion neurons undertake promiscuous innervation of which, with positive feedback, acts upon P2Y2 and/or P2Y4

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receptors to promote further Ins(1,4,5)P3 production via (e.g. to different adequate stimuli). Rather, the puriner-
the Gq–PLCb–Ins(1,4,5)P3 pathway and Ca2+ release gic system seems to be a phylogenetically old and rather
[131]. Rapid propagation of the Ca2+ signal occurs as universally usable and versatile ‘tool’ to control the de-
ATP diffuses to adjacent cells. The propagation of Ca2+ velopment and diverse cellular interactions of the
waves can be blocked by apyrase [132], as shown for the vertebrate nervous system and fine-tune information
ATP release in Kőlliker’s organ during development [126]. processing within it.
This extracellular ATP-dependent Ca2+-signaling mech-
anism can be invoked by the death of a single hair cell [132] Acknowledgements
and might reflect a cochlear tissue-injury response. The This work was supported by the Deutsche Forschungsgemeinschaft (RE
849/12; GRK 1097/1; www.dfg.de/en) grants to A.R., by the
oscillatory Ca2+ waves in the organ of Corti supporting Bundesministerium für Bildung und Forschung (DLR/01GZ0703;
cells and outer sulcus evoke a variety of spatiotemporal www.bmbf.de) grant to A.R., by the Interdisziplinäres Zentrum für
injury responses in the tissue, including activating mem- Klinische Forschung (www.izkf-leipzig.de) at the Faculty of Medicine of
bers of the mitogen-activated protein kinase pathway, the University of Leipzig (C35, Z10) grant to A.B., and by National
including c-Jun N-terminal kinase (JNK) activity and Health and Medical Research Council, Australia (www.nhmrc.gov.au),
Health Research Council, New Zealand (www.hrc.govt.nz) and Marsden
extracellularly regulated kinases 1 and 2 (ERK1/2) Fund (Royal Society of New Zealand; www.marsden.rsnz.org) grants to
[132,133], leading to hair-cell encroachment and scarring G.D.H. Graphic contributions by Jens Grosche is gratefully
of the reticular lamina. acknowledged.
Adenosine is otoprotective. In the cochlea, it can be
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