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Purinergic signaling in special sensesGary D. Housley1, Andreas Bringmann2 and Andreas Reichenbach3
1 Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, Faculty of Medicine,
University of New South Wales, Sydney, NSW 2052, Australia2 Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrae 10-14, D-04103 Leipzig,Germany3 Paul Flechsig Institute of Brain Research, Faculty of Medicine, University of Leipzig, Jahnallee 59, D-04109 Leipzig, Germany
We consider the impact of purinergic signaling on the
physiology of the special senses of vision, smell, taste
and hearing. Purines (particularly ATP and adenosine)
act as neurotransmitters, gliotransmitters and paracrine
factors in the sensory retina, nasal olfactory epithelium,
taste buds and cochlea. The associated purinergic re-
ceptor signaling underpins the sensory transduction and
information coding in these sense organs. The P2 and P1
receptors mediate fast transmission of sensory signalsand have modulatory roles in the regulation of synaptic
transmitter release, for example in the adaptation to
sensory overstimulation. Purinergic signaling regulates
bidirectional neuronglia interactions and is involved in
the control of blood supply, extracellular ion homeosta-
sis and the turnover of sensory epithelia by modulating
apoptosis and progenitor proliferation. Purinergic sig-
naling is an important player in pathophysiological pro-
cesses in sensory tissues, and has both detrimental (pro-
apoptotic) and supportive (e.g. initiation of cytoprotec-
tive stress-signaling cascades) effects.
Introduction
The past two decades were witness to a rapid accumulation
of data showing that purinergic signaling is an essential
and crucial factor throughout the vertebrate nervous sys-
tem. Purines and pyrimidines acting at purinergic P1 and
P2 receptors are extracellular signaling molecules involved
in nearly every aspect of development, pathophysiology,
neurotransmission and neuromodulation [1,2]. Adenosine
(P1) receptors are subdivided into four subtypes (A1, A2A,
A2B and A3), all of which couple to G proteins. P2 receptors
(recognizing primarily adenine and uracil tri- and dinu-
cleotides) comprise two families: ionotropic P2X and G-
protein-coupled P2Y receptors. P2X receptors (which
represent ATP-gated ion channels) are subdivided into
seven subtypes (P2X1 to P2X7); P2Y receptors compriseat least eight subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11,
P2Y12, P2Y13 and P2Y14). These subtypes differ in their
molecular structure and selectivities to agonists and
antagonists [1]. P2X receptors contribute to fast excitatory
synaptic transmission and also act presynaptically to
modulate neurotransmitter release, whereas P2Y recep-
tors are involved in neuromodulation and neuronglia
interactions. Adenosine has a key role in the regulation
of tissue oxygenation, neuronal firing, neurotransmitter
release and cytoprotective responses. ATP is released as a
cotransmitter via vesicle-mediated exocytosis from synap-
tic terminals, and from non-neuronal cells by secretion of
vesicles or calcium-independent mechanisms via plasma-
membrane nucleotide-transport proteins, connexin or pan-
nexin hemichannels, anion channels and other processes
[2]. Adenosine can be released by nucleoside transporters
or is formed extracellularly from ATP by ecto-nucleoti-
dases [2]. Degradation of nucleotides by ecto-nucleotidases
also provides rapid termination of purinergic signaling [2].
As in the brain, purinergic receptors are abundant in thetissues of special senses. Here, we aim to critically evaluate
what is presently known (and proposed) about the path-
ways and roles of purinergic signaling in the special sense
organs of vision, olfaction, taste and hearing. These can be
part of the central nervous system such as the retina or of
the peripheral nervous system such as the inner ear, the
olfactory epithelium and taste buds. Moreover, the charac-
teristics of the stimulus in addition to the degree of local
information processing differ greatly among the senses.
Joint review of purinergic signaling in these sensory sys-
tems provides an opportunity to consider which roles are
adaptations to specific purposes and which are general
features of the nervous tissue.
Vision
In the sensory retina, purines are tonically released in
darkness; the release increases with neuronal activity [3].
ATP is liberated from neurons in a Ca2+-dependent man-
ner [3,4] and from glial and pigment epithelial cells by
Ca2+-independent mechanisms [58]. Adenosine might be
released via nucleoside transporters by ganglion and glial
cells [8], and it can be formed enzymatically in the extra-
cellular space from ATP [911]. Ecto-nucleotidases have
been localized to both plexiform (synaptic) layers [1214].
Neurotransmission and neuromodulation
In the retina, photoreceptors, most neurons, glial cells, the
microvasculature and pigment epithelial cells express P1
and P2 receptors (Table 1). ATP is likely to contribute to
fast excitatory neurotransmission by activation of P2X
receptors and has a potential neuromodulatory role acting
at P2Y receptors localized to neuronal and supportive cells
(Figure 1; Table 1). However, the role of purines in reg-
ulating retinal function is not well determined. Under-
standing the function of ATP in the retina is also
complicated by species differences. It has been suggested
that various P2X receptor subtypes are differentially
involved in specific circuits within the retina; P2X7 might
preferentially modulate signal transmission in the rod
Review
Corresponding author: Housley, G.D. ([email protected]).
128 0166-2236/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.01.001 Available online 18 February 2009
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Table 1. Expression of purinergic receptor subtypes in different cell types of the sensory retina a
Receptor subtypes Species Localization and functional activity Refs
Photoreceptors
A1, A2 Salamanderb,c Inhibition of L-type Ca2+ currents and glutamate release from rods [21]
A2 Rabbitd and moused Inner and outer segments of photoreceptors [140]
A2 Teleostse Induction of cone elongation in dark; increase in cAMP level [141]
A2A Salamanderf Inhibition of opsin mRNA expression in rods at night; increase
in cAMP level
[142]
P2X2 Ratf,g Somata and outer segments of photoreceptors [143]
P2X7
Rat and marmosetg,h,i Increase in the amplitude of the ERG a-wave [12,16]
P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j, rabbitf and
macaquefInner segments of photoreceptors [144146]
Bipolar cells
A1 Ratc Suppression of NMDA-mediated currents [26]
P2X3, P2X 4, P2X 5 Ratj Not determined [147]
P2Y1, P2Y2, P2Y4, P2Y6 Ratg,h,j Not determined [148,149]
Retinal ganglion cells
A1, A2A, A3 Ratf and mousek Not determined [150,151]
A1 Ratb,c Inhibition of voltage-dependent Ca2+ channels and of the
glutamate-induced increase in cytosolic Ca2+; activation of K+ channels;
decrease in the spike activity
[9,10,23]
A1 Salamander2 Inhibition of N-type Ca2+ channels [22]
A3 Ratb Inhibition of P2X7-receptor-mediated Ca
2+ rise and ganglion cell death [58]
P2X2, P2X3, P2X4,
P2X5, P2X 7
Ratf,g,j Not determined [15,143,152154]
P2X7Ratb,g Sustained increase in cytosolic Ca2+; activation of L-type Ca2+ channels
and of caspases; cell death
[57]
P2X7 Mouseg,j Not determined [155]
P2Y1, P2Y2, P2Y4, P2Y6 Ratf,g,j Not determined [145,148]
Amacrine cells
A1 Chickb,e and rabbite Inhibition of N-type Ca2+ channels and PLC; inhibition of ACh release [4,24,25]
P2X1, P2X2, P2X3,
P2X5, P2X7
Ratg,h and mouse6 Not determined [13,15,156,157]
P2X2 Mouseg Inhibition of ACh release from OFF cholinergic amacrines [17,18]
P2X7 Ratg,h,j Not determined [16,154]
Horizontal cells
P2X7 Monkeyg ratg,h Not determined [16,153]
Interplexiform cells
P2X3 Ratg,h Not determined [13]
Retinal astrocytes and Muller cells
A1 Rate Inhibition of osmotic cell swelling; activation of K+ and Cl channels [14,31,158]
A1, A2A, A2B Rat
b,c
Potentiation of light-evoked Ca
2+
responses [20]A2 Rat
b Elicitation of Ca2+ waves [159]
P2X7 Humanb,c Ca2+ influx; cell depolarization; activation of BK channels; stimulation
of cell proliferation
[47,160]
P2Y1, P2Y2, P2Y4,
P2Y6, P2Y11, P2Y13
Salamanderb Elicitation of Ca2+ waves [161,162]
P2Y1, P2Y2, P2Y4, P2Y6 Ratb,j Elicitation of Ca2+ responses [8,148,159,164]
P2Y1 Rate Inhibition of osmotic cell swelling; stimulation of transporter-mediated
release of adenosine
[8,31]
P2Y1, P2Y2, P2Y4, P2Y6 Humanb,c,g,j Elicitation of Ca2+ responses; activation of BK channels [163,165]
Retinal microglia
P2X7 Rate Formation of transmembrane pores; induction of apoptosis; release
of inflammatory cytokines (e.g. TNFa, interleukin-1b)
[166,167]
P2Y2, P2Y4 Rate Stimulation of cell proliferation [167]
P2Y1 Rabbite Retraction of cell processes [168]
Pericytes of retinal microvasculature
A1, A2A Ratc
Hyperpolarization of pericytes; opening of KATP channels [30]P2X7, P2Y4 Rat
b,c Pericyte depolarization and contraction; Ca2+ responses [169]
P2X7, P2Y4 Ratb,c P2X7: formation of transmembrane pores; activation of
voltage-dependent Ca2+ channels and lethal Ca2+ influx
[170]
P2Y4: inhibition of P2X7 pore formation
Retinal pigment epithelium
A1, A 2 Humanb,e Potentiation of ATP-evoked Ca2+ responses [171]
A2 Pige Increase in cAMP level [172]
A2B Rate Inhibition of phagocytosis of outer segments; increase in cAMP level [173]
P2X, P2Y Ratb,c P2X: nonselective cation conductance [174]
P2Y: release of Ca2+ from internal stores; activation of BK currents
P2Y1, P2Y2, P2Y4,
P2Y6, P2Y12
Humanb,j,l Ca2+ responses [175]
P2Y2 Cowb,c, humanb,c
and rabbite,fCa2+-dependent increase in Cl conductance and decrease in K+
conductance; stimulation of the transcellular fluid transport
[36,37,176]
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pathway and P2X2 in the cone pathway[12,15,16]. P2X7 is
expressed by nearly every type of retinal neuron (Table 1).
In the rat retina, P2X7 was localized to photoreceptor
terminals near the ribbon synapse, to horizontal cells
invaginating the photoreceptor terminals and to amacrine
cells that provide synaptic input onto the rod bipolar
terminal [12,16]. P2X7 receptor activation results in an
increase of the photoreceptor-derived a-wave of the elec-troretinogram and in transient reduction of the photo-
receptor-derived postsynaptic responses [15].
In the mouse retina, ATP might modulate signal pro-
cessing of the ON and OFF pathways in an asymmetrical
manner. The immunohistochemical distribution of dis-
tinct P2X receptor subtypes differs between the ON and
OFF pathways, with a selective enrichment of P2X2 in
OFF cholinergic amacrines [17,18]. Here, ATP increases
g-aminobutyric acid (GABA)ergic inhibitory postsynaptic
currents in OFF but not ON cholinergic amacrines, and
suppresses OFF ganglion cells but activates ON ganglion
cells [17]. In the rat retina, P2X2 is localized to GABA-
ergic amacrine cells (that form synapses with cone but
not rod bipolars) and a population of ganglion cells [15]. Afurther unresolved problem is the source(s) of ATP
involved in synaptic transmission. It has been speculated
that ATP is co-released with GABA from GABAergic
amacrines and horizontal cells [16], with acetylcholine
from cholinergic amacrines [19] and, possibly, from
ganglion cells [20].
Table 1 (Continued)
Receptor subtypes Species Localization and functional activity Refs
Developing retina
A2 Ferret, mouseb,g Increase in the spontaneous activity of ganglion and amacrine cells
by stimulation of adenylyl cyclase and PKA activity
[177]
A2A Chicke Increase in the survival of developing retinal neurons; increase
in cAMP level
[178]
P2Y1 Xenopusm Initiation of eye formation; expression of Pax6 and Rx1 [39]
P2Y1 Chicke Stimulation of the proliferation of late progenitors; activation of PLC,
PKC and ERKs
[43,44]
P2Y2, P2Y4 Chickb,e Stimulation of the proliferation of early progenitors [7,40,41]
aAbbreviations: ACh, acetylcholine; BK, Ca2+-activated K+ channels of large conductance; cAMP, cyclic AMP; ERG, electroretinogram; ERK, extracellular signal-regulated
kinase; KATP, ATP-sensitive K+ channels; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.
Expression of purinergic receptors was identified by the following methods:bCa2+ imaging; celectrophysiology; dradioligand labeling; epharmacology; fin-situhybridization;gimmunohistochemistry; helectron microscopy; ienzyme histochemistry; jRTPCR; ktransgene expression; lwestern blotting; mreceptor knockdown.
Figure 1. Purinergic signaling in the retina. The following purinergic paths are symbolized by the arrows: (1) modulation of processes of transduction in the photoreceptor
cells; this involves A1 and A2 receptors and several types of P2X and P2Y receptors; the probable agonist sources are glial and/or RPE cells; (2) modulation of signal
processing in the OPL; this involves A1, A2 and P2X7 receptors; the agonist source(s) is unknown; (3) modulation of signal processing in the IPL; this involves A1 and several
types of P2X receptors; the agonist source(s) is unknown; (30) modulation of cholinergic amacrine cells; this involves A1 and P2X2 receptors; the signaling source(s) is
unknown; (4) neuron-to-glia signaling; this involves A1, A2 and several P2Y receptor subtypes; the probable source of agonists are ganglion and amacrine cells; (5) autocrine
signaling in Mu ller glial cells (e.g. for volume regulation); this involves P2Y1 and A1 receptors; (6) glia-to-glia signaling (e.g. Ca2+ waves) of astrocytes and Mu ller cells; this
involves P2Y receptors; (60) signaling (e.g. Ca2+ waves) between RPE cells; (7) glia-to-neuron signaling, arising from Mu ller cells; this involves A1 receptors and not yet
specified P2X receptors; (8) glia-to-blood vessel signaling (control of blood flow), arising from astrocytes and Mu ller cells; (9) control of RPE functions including water
clearance from subretinal space; this involves P2Y2 receptors; the agonist source(s) is unknown; and (10) control of progenitor and Mu ller cell proliferation; this involves
several types of P2Y receptors (and, in culture, P2X7 receptors); the agonist source(s) is unknown. Abbreviations: A, amacrine cells; AS, astrocyte; B, bipolar cells; BV, blood
vessel; C, cone photoreceptor cell; G, retinal ganglion cells; GCL, ganglion cell layer; H, horizontal cell; INL, inner nuclear layer; IPL, inner plexiform layer; M, Mu ller cell;
OFF, sublayer of the IPL where light-off information is processed; ON, sublayer of the IPL where light-on information is processed; ONL, outer nuclear layer; OPL, outer
plexiform layer; PRS, photoreceptors segments; R, rod photoreceptor cell; RPE, retinal pigment epithelium.
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Adenosine suppresses excitatory neurotransmission in
the retina by various mechanisms (Table 1) including
inhibition of presynaptic voltage-dependent calcium chan-
nels resulting in reduced transmitter release, for example
of glutamate [2123], acetylcholine [4,18,24,25] and ATP
[4]. Adenosine inhibits the activity of N-methyl-D-aspar-
tate (NMDA) receptors [23,26] and phospholipase C [25],
and increases the activity of GABAAreceptor channels [27]
and KATP (ATP-sensitive K+) channels [28].
Neuronglia signaling and supportive functions
Purinergic signaling might be implicated in the bidirec-
tional dialogue between neurons and glial cells in the
retina. Flickering light was shown to increase the fre-
quency of Ca2+ transients in glial cells, which is likely to
be mediated by ATP released from neurons and sub-
sequent activation of P2Y receptors [20]. The purinergic
neuron-to-glia signaling might trigger an activation of glial
cells implicated in the light-evoked dilation and constric-
tion of retinal arterioles (neurovascular coupling) [29].
Adenosine increases the retinal blood flow through relaxa-
tion of pericytes [30]; a contribution of glia-derived adeno-sine, released in response to glutamate [8,31], remains to
be confirmed.
Purines released from retinal glial cells were suggested
to modulate synaptic activity [9]. Activation of glial cells,
for example by glutamate or electrical and mechanical
stimulation, triggers intercellular Ca2+ waves in the glial
network [32,33]. The propagation of the waves depends
upon the release of ATP and activation of P2Y receptors
[5,32] and is associated with an alteration in the light-
evoked activity of ganglion cells [33]. ATP released from
activated glial cells into the inner plexiform layer [5,9]
might be converted extracellularly to adenosine that acti-
vates A1 receptors in a population of ganglion cells, result-
ing in a depression of spontaneous activity [9,10].
Purines also regulate supportive functions of retinal glial
and pigment epithelial cells. Glutamatergic neurotrans-
mission in the retina is associated with changes in cellular
and extracellular volume [31,34] and with a decrease in the
osmolarity of the extracellular fluid [35]. Retinal glial cells
possess a purinergic signaling mechanism that maintains
their volume constant, to prevent a detrimentalshrinkage of
the extracellular space under hypo-osmotic conditions [34].
This mechanism involves the release of ATP and adenosine
and the autocrine activation of P2Y1 and A1 receptors [8,31]
and can be triggered by glutamate derived from neurons or
glial cells [31,34]. Activation of P2Y1, P2Y2 and A1 receptors
stimulates the absorption of excess fluid from the retinaltissue across the pigment epithelium [36,37] and, probably,
by glial cells [38]. This is required to redistribute metabo-
lically generated water (to prevent edema formation) and to
maintain a proper attachment of the neuroretina to the
pigment epithelium.
Retinal development
Purinergic signaling is involved in the early eye formation
and retinal development. In Xenopus laevis, ADP, extra-
cellularly formed from ATP, triggers the expression of the
eye field transcription factors Pax6 and Rx1, which are
necessary for eye development [39]. In the chick, ATP
stimulates the proliferation of early retinal progenitors
(by activation of P2Y2 and/or P2Y4 receptors) [7,40,41]
and of late glial and bipolar progenitors (by P2Y1 receptors)
[4244]. The division of progenitor cells in the ventricular
zone of the chick retina is likely to be stimulated by ATP
released from the pigment epithelium [7,45].
Retinal pathophysiology
Cellular proliferation is a common response of retinal glialcells to pathogenic stimuli involved in the formation of glial
scars [46]. Glial cell proliferation is stimulated by ATP
[47,48]; a bidirectional interaction between P2Y and
growth factor receptors seems to be involved in this effect.
The mitogenic effect of ATP depends on a release of growth
factors and on transactivation of growth factor receptor
tyrosine kinases [49], whereas growth factors trigger a
rapid resensitization of P2Y receptors, which are desensi-
tized by ATP [50]. However, the involvement of these
mechanisms in retina injuries in situ remains to be deter-
mined. Retinal gliosis in situ is characterized by an early
increase in P2-receptor-mediated Ca2+ responses
[47,51,52] indicating that ATP is one signal that initiatesretina protection and repair.
Excess ATP, released in response to pathogenic factors
such as mechanical perturbations [5,9] and elevated intra-
ocular pressure [5355], might be also implicated in
neuronal degeneration. P2X receptors are highly Ca2+
permeable [56]. Prolonged activation of P2X7 receptors
induces retinal ganglion cell death via Ca2+-dependent
mechanisms [57]. ATP-evoked ganglion cell death could
be involved in glaucoma [53]. The balance between extra-
cellular ATP and adenosine levels might determine the
level of ganglion cell death because adenosine inhibits the
P2X7-receptor-mediated Ca2+ rise and apoptosis of
ganglion cells [58]. However, whether ATP would be
released in levels high enough to overcome rapid conver-
sion to adenosine is not known. A rapid release of adeno-
sine is an important component of the retinal response to
ischemia or hypoxia [11,59]. Adenosine induces retinal
hyperemia after ischemia [60] and might protect neurons
from glutamate toxicity by suppression of excitatory neuro-
transmission. Activation of A1 and/or A2 receptors, or
ischemic preconditioning mediated by endogenous adeno-
sine and A1 receptor activation, protects the retina from
ischemic injury [28,61,62].
Olfaction
The nose of vertebrates utilizes various systems for che-
mosensation including the main olfactory system, vomer-onasal organ, Gruneberg ganglion and trigeminal system.
The main olfactory epithelium consists of olfactory recep-
tor neurons, glia-like sustentacular cells, microvillar cells
and basal cells. Here, extracellular ATP might be released
from receptor neurons and their axons [63,64], from sym-
pathetic and trigeminal nerve fibers [6567] and from cells
that are acutely injured by toxic compounds, for example
highly concentrated odorants [68]. It has been suggested
that there is a constant low level of extracellular ATP in the
main olfactory epithelium that induces a tonic suppression
of the activity of receptor neurons [69] and trigeminal
fibers [63].
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In the main olfactory epithelium, ATP could activate
multiple P2 receptor subtypes expressed by receptor
neurons, sustentacular cells, basal cells (Figure 2;
Table 2), solitary microvillar cells [70] and trigeminal
nerve fibers. Activation of P2X and P2Y receptors in mur-
ine olfactory receptor neurons evokes inward currents and
cytosolic Ca2+ responses and reduces the odorant-induced
activity of the cells [69]; this indicates that P2 receptors
modulate odor sensitivity implicated, for example, in odor
adaptation. P1 and P2 receptors might also be involved in
olfactory receptor trafficking [71]. In sustentacular cells,
ATP evokes Ca2+ responses [69,72] and the opening of gap
junctions, thus enhancing the functional coupling between
the cells [73]. ATP released from injured cells could initiate
protective responses such as (i) reduction of the odorant
sensitivity of receptor neurons [69], (ii) induction of heat-
shock proteins in sustentacular cells, which might facili-
tate inhalant detoxification [68] and (iii) stimulation of
basal cell proliferation to regenerate the damaged tissue
[69]. Chemosensory trigeminal neurons express P2X2receptors; the suppression of P2X2 receptor currents by
distinct odorants might contribute to central odor recog-
nition [63]. In the vomeronasal organ, primary olfactory
neurons and secretory cells express purinergic receptors
[74].
Taste
Multiple purinergic signaling pathways contribute to the
coding and transmission of taste sensation, particularly for
taste buds, which occur on the tongue (lingual), palate and
larynx [75] (Figure 3; Table 3). In the taste bud, ATP is
released as a neurotransmitter and as a paracrine signal
for coupling taste cells with differing transduction modal-ities and gliasensory-cell communication. This occurs via
a non-vesicular mechanism involving pannexin 1 [76] and
connexin [77] hemichannels. Chemosensory cells and
fibers in the oral cavity and upper alimentary tract also
contribute to taste and broader chemosensory transduc-
tion, but with limited modality and less compelling evi-
dence for purinergic signaling.
ATP release from taste-bud type II receptor cells (TR-
expressing cells) is central to the coding of sweet, bitter and
umami taste, acting directly on P2X2 and P2X3 hetero-
meric receptors at the chemosensory afferent terminals
[75] of the chorda tympani branch of the facial nerve (n.
VII) and in the posterior aspect of tongue via glossophar-
yngeal (n. IX) innervation. The sweet modality utilizes the
T1R2T1R3 receptor dimer, with bitter tastes transduced
via a large family of T2R receptors and umani (the meati-
ness of monosodium glutamate) attributed to an N-term-
inal variant of the metabotropic glutamate mGlu4 receptor
and the T1R1T1R3 receptor dimer; these are all G-protein
coupled (for review, see Ref. [78]). In a P2X2/P2X3 double
knockout mouse model, all gustatory transmission was lost
from lingual taste buds [75]. Although the type II taste-bud
TR-expressing cells do not possess synaptic proteins,
recent transgenic mouse studies using T1R3 promoter/
enhancer-driven wheat germ aglutinin expression con-
firmed the intimate coupling of the sweet and umami type
Figure 2. Purinergic signaling in the olfactory epithelium. The following purinergic
paths are symbolized by the arrows: (1 and 10) modulation of signal integration
and/or firing rate; this involves several types of P2X and P2Y2 receptors; the
agonist source(s) might be other ORNs and/or efferent nerves; a possible
purinergic glia-to-neuron signaling remains to be determined; (2) neuron-to-glia
signaling might involve several types of P2X and P2Y1 and P2Y2 receptors; the
agonist source(s) is probably ORNs; (3) glia-to-glia signaling among the
sustentacular cells (Ca2+-wave-induced modification of gap-junctional coupling);
and (4) control of progenitor cell proliferation; this involves P2X1 and P2Y2receptors; the agonist source(s) might be ORNs and/or SCs. Abbreviations: BC,
basal cell; DK, dendritic knob; ORN, olfactory receptor neuron; SC, sustentacular
cell; TB, tubular bone.
Table 2. Expression of purinergic receptor subtypes in the main olfactory epitheliuma
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 Ratd Not determined [74]
Sustentacular supporting cells
P2X5, P2X7, P2Y1 Ratd Not determined [74]
P2Y Mouseb,c Elicitation of Ca2+ responses; activation of BK channels; opening of gap junctions [69,73]
P2Y2, P2Y4 Moused, Xenopusb Elicitation of Ca2+ responses [69,72]
Basal cells
P2X1, P2Y2 Moused Not determined [69]
P2X7 Ratd Not determined [74]
aAbbreviations: BK, Ca2+-activated K+ channels of large conductance.
Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dimmunohistochemistry.
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II receptor cells to the P2X-receptor-expressing intragem-
mal nerve fibers of the taste buds [79,80]; this is indicative
of direct purinergic transmission, albeit with unconven-
tional synaptic connectivity.
P2Y receptors probably modulate ATP (transmitter)
release via autocrine and paracrine feedback via the phos-
pholipase C (PLC)b2Ins(1,4,5)P3 [inositol (1,4,5)-trispho-
sphate]-receptor-3-gated Ca2+-store pathway. Several G-
protein heterotrimers are implicated in taste transduction
and add breadth to the response characteristics, whereas
transduction of the other two modalities (i.e. sour and
salty) involves additional transduction pathways [78].
The most notable markers of the taste-bud receptor cells
are the T1Rs, T2Rs, the bitter tastant G protein a gustdu-
cin, sweet tastant Ga14 [81], PLCb2 and the Ca2+-gatedtransient receptor potential channel TRPM5. The Ca2+
signal for triggering ATP release is likely to include the
TRPM5 channel and voltage-gated Na+ channels [77];
concurrent elevation of cytosolic Ca2+ and membrane
depolarization activate Px1 [82]. Encoding of tastant
responses might reflect the generator potential activity
of the receptor cells. Although receptor cells do not express
G-protein-coupled receptors for different tastant modal-
ities, there will be multi-modal integration of the tastant
responses at the chemoreceptor afferents because the same
fiber innervates multiple receptor cells [78] and the TR-
expressing cells and type III (presynaptic) taste cells are
coupled via P2X- and P2Y-receptor-mediated paracrinesignaling.
In addition to the direct coupling of the taste-bud TR-
expressing (type II) cells to a subset of purinergic intragem-
mal fibers, paracrine ATP signaling to the adjacent presyn-
aptic cells is likely to modulate the serotonergic
transmission at these conventional synapses via activation
of P2X and P2Y receptors. Ca2+ entry and release of Ca2+
from Ins(1,4,5)P3-gated stores provides a stimulus that
drives exocytosis of serotonin-containing synaptic vesicles
[76,78]. Serotonin might then activate chemoreceptor affer-
ents (as yet unconfirmed), and additional local release of
serotonin might itself have paracrine action within the taste
bud via serotonin 5-HT1 receptors [78,83]. The presynaptic
cells directly transduce tastants. For example, each taste
bud contains several of these cells that express the putative
sour-sensing TRP channel PKD2L1 [84]. Analysis of P2X
and P2Y expression highlights the functional coupling be-
tween all types of taste receptor cells. Given that each
mammalian taste bud contains $80 cells, ATP will diffuse
to adjacent receptor, synaptic and glial (type I) cells, in
addition to the precursor (type IV) cells, activating the full
range of these purinergic receptors, depending upon agonist
type (e.g. ATP versus ADP) and concentration.
It is notable that functional P2X7 receptor expression
has been identified in the mouse fungiform taste-bud cells,
implicating this pathway in the apoptotic mechanisms
associated with their rapid turnover [85]. These are prob-
Figure 3. Schematic summary of purinergic signalingin thetastebud.The following
purinergic paths are symbolized by the arrows: ATP is released from the (type II)
taste-bud receptor cells viapannexin1 (and connexin)hemichannels and(1) actsas a
neurotransmitter directly on the nerve endings of purinergic chemosensory afferent
fibers (via P2X2 and P2X3 receptors) to encode sweet, bitter and umami tastants; (2)
released ATP also has an autocrine and paracrine action on the receptor cells andprovides a coupling signal to the presynaptic (type III) taste-bud cells that release
serotonin as a neurotransmitter and neuromodulator (these are predominantly sour-
sensing cells);this is mediated by activation of P2X2 and P2Y1 receptorsto produce a
Ca2+ signal; (3) ATP autocrine action via P2Y1, P2Y2 and P2Y4 receptors to regulate
ATP release; (4) the enshrouding glial (type I) cells signal to the type IV cells, which
stimulate these precursor cells to sustain the replacement of the high turnover of
taste receptor cells; and (5) high levels of NTPDase2 on the cell surface of the type I
cells terminate the ATP signal.
Table 3. Expression of purinergic signaling elements in taste
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 Rate Chemosensory (taste) afferent [179,180]
P2X2P2X3 heteromer Mousee,g Chemosensory (taste) afferent [75]
Bud cells
Fungiform, circumvallate and foliate papillae
P2X2, P2X7 Mousea,b,c,e,f P2X2 on presynaptic cells fungiform papilla; P2X7 cell subtype not specified [85]
P2Y1 Rata,d,e,f Expressed in a subset of taste receptor and presynaptic cells; Ca 2+ increase with ATP [181]
P2Y1, P2Y2, P2Y4, P2Y6 Mousee,f Four dominant P2Y receptors; equally co-expressed in $75% of circumvallate and foliate
papillae taste-bud cells; Ca2+ responses
[85,182]
Expression of purinergic receptors was identified by the following methods: aCa2+ imaging; belectrophysiology; cpharmacology; din-situhybridization; eimmunohistochem-
istry; fRT-PCR; greceptor knockout.
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ably presynaptic cells based on negative results (no change
in current) of theP2X7-selective agonist BzATP withvoltage
clamp of receptor cells from circumvallate taste buds [77].
ATP signaling within the lingual, palatal and laryngeal
taste buds is terminated by an ATP-selective ecto-nucleoti-
dase. An initial histochemical characterization of Ca2+-de-
pendent ecto-ATPase activity in taste buds from the golden
hamster showed strong labeling of the glial cells that
ensheath the receptor and presynaptic cells [86]. Genetranscript screening of taste-bud-enriched tissue, enzyme
activity assays and immunocytochemistry in mouse sub-
sequently identified this principally as nucleoside tripho-
sphate diphosphohydrolase-2 (NTPDase2), which is highly
selective for ATP over ADP [87]. Thus, ATP signaling is
tightly constrainedwithin thetastebud andunlikely to spill
overto activate purinergic sensory fibers for touch, tempera-
ture and pain [88].
Hearing
The cochlea exhibits a diverse array of purinergic signaling
components. This includes all sevenionotropic P2X receptor
subunits and all studied metabotropic P2Y receptors, inaddition to P1 receptor signaling via adenosine arising, in
part, from conversion of nucleotides by ecto-nucleotidases.
Figure 4 and Table 4 highlight important purinergic sig-
naling mechanisms supporting the maintenance of sound
transduction and neurotransmission in the cochlea.
Purinergic modulation of auditory neurotransmission
A role for extracellular ATP as an effector of cochlear
neurotransmission was identified earlier than glutamate
[89]. Perfusion of the scala tympani (i.e. into the perilymph)
with P2X receptor agonists and antagonists suppresses and
enhances, respectively, the compound action potential
[90,91], supporting a role for regulation of primary afferent
neurite excitability [91]. In the adult rat and guinea-pig
spiral ganglion neurons, the predominant P2X receptors are
P2X2 andP2X7. Agonists of P2X2,butnotP2X7, have a direct
action on individual afferent auditory fibers affecting the
breadth of the tuning curve [92]. P2X2 has been localized to
the postsynaptic specializations at the spiral ganglionneuron neuritehair-cell synapses at both inner and outer
hair cells [93], and both type I and type II spiral ganglion
neurons exhibit ATP-gatedinward currents at thecell soma
[94]. Glucocorticoids enhance the P2X receptor signaling
and elicit nitric oxideproduction by the cells, which provides
local signaling[95], potentially interacting withthe satellite
glial cells. P2Y receptor activation in the soma of the spiral
ganglionneurons elicits Ca2+ signaling[96], which recruits a
substantial nonselective cation conductance, impacting on
primary afferent excitability [97]. The outer hair cells are
also innervated by cholinergic (olivocochlear) efferent fibers
that act to reduce hearing sensitivity by modulating outer
hair cell-mediated reverse transduction. P2X7 receptorexpression occurs presynaptically[98] and might influence
this neural feedback.
Paracrine signaling supports cochlear homeostasis
In the rodent cochlea, both P2X and P2Y receptors are
extensively expressed in the cochlear partition, and via
autocrine and paracrine action they are likely to reduce the
driving force forsound transduction when stressors such as
acoustic overstimulation or ischemia cause the release of
ATP into the scala media. P2X2 receptors, in particular, are
Figure 4. Schematic summary of purinergic signaling in the cochlea. The following purinergic paths are symbolized by the arrows: (1) ATP in marginal cells is contained in
vesicles and provides autocrine and paracrine action to inhibit K+ influx into the scala media by a P2Y4 receptorPLC PKC pathway closing KCNE1/KCNQ1 K+ channels; this
acts in synergy with pathway (5); (2) internal K+-transport regulation within the stria vascularis; this is via the P2Y4 receptor; (3) strial blood vessels; A2A-receptor-mediated
vasodilatation with ischemia; (4) regulation of K+ recycling between perilymph and endolymph via Ca2+ signaling and connexins in the spiral limbus and spiral ligament;
this is via A1, P2X2 and P2Y receptors; (5) K+ shunt out of the endolymph via ATP-gated nonselective channels (which decreases the EP and depolarizes hair cells) works in
synergy with pathway (1); this is mediated by the P2X2 receptor; (6) autocrine action: multiple signaling pathways within the hair cells and adjacent supporting cells affect
the membrane potential and micromechanics of the hair cells and supporting cells, Ca 2+ and nitric oxide signaling; this is via P2X2 and P2X7, and P2Y2 and P2Y4 receptors;
(7) paracellular epithelial ion homeostasis in inner and outer sulcus (connexin and pannexin 1 hemichannels); Ca2+ waves and K+ re-absorption during acoustic
overstimulation; this is via P2X2 and P2Y4 receptors; (8) postsynaptic actions at the afferent (spiral ganglion) neurites and terminals at the hair cells (neuromodulation);
during synaptic consolidation before hearing onset, activity to inhibit neurite extension by blocking Trk signaling of neurotrophins; this is via P2X2 and P2X2/P2X3 receptors;
(9) spiral ganglion neuronneuron or satellite cell (glia)-to-neuron signaling; Ca2+ signaling activates BK channels, regulating spontaneous activity; via A1, A2A and A3, P2X2and P2X7 receptors (P2X1 and P2X3 during development) and the P2Y receptor; and (10) efferent fiberhair cell presynaptic regulation of cholinergic efferent inhibition of
outer hair-cell electromotility; this is via the P2X7 receptor. Abbreviations: BM, basilar membrane; BV, blood vessel; DC, Deiters cell; HC, Hensens cell; IDC, interdental cells;
IHC, inner hair cell; IS, inner sulcus; ISP, inner spiral plexus; OHC, outer hair cell; RM, Reissners membrane; SGN, spiral ganglion neuron; ScM, scala media; ScT, scala
tympani; ScV, scala vestibuli; SLG, spiral ligament; SP, spiral prominence; SV, stria vascularis; TM, tectorial membrane.
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highly expressed on the apical surfaces of the cells facing
the endolymphatic compartment. This includes Reissners
membrane (a two-cell-thick resistive barrier between the
scala media and scala vestibuli), in addition to the inner
and outer sulcus regions and hair cells of the organ of Corti
[93,99,100]. All these cells have tight junctions that main-
tain the integrity of the endolymphatic compartment. The
adjacent stria vascularis has a K+ transporter system that
generates the endocochlear potential (EP;$+100 mV). The
EP provides the majority of the driving force for sound
transduction [101]. Physiological experiments and bio-
chemical analysis has shown that the ionotropic and meta-
botropic signaling pathways act in synergy to regulate
electrochemical homeostasis. ATP released into this com-
Table 4. Expression of purinergic signaling elements in the cochleaa
Receptor subtypes Species Localization and functional activity Refs
Reissners membrane
Epithelial cells
P2X1, P2X2 Rate,f Transient downregulated by P10 [183]
P2X2 Rate K+ shunt from endolymph, protection against acoustic overstimulation [184]
P2X2 Guinea-pigc,f,h K+ shunt from endolymph, protection against acoustic overstimulation [185]
P2X2 Mousei K+ shunt from endolymph, protection against acoustic overstimulation Housley, G.D.
et al. (abstract)j
Stria vascularis: marginal, intermediate and basal cells
P2Y2, P2Y4 Gerbil, ratc,f P2Y4 on apical surface inhibits KCNE1/KCNQ1 K
+ channel via PKC; protection
against acoustic overstimulation
[108,186]
Endothelial cells of the strial blood vessels
A2A, A3 Ratf Vasodilatation [135]
Spiral ligament (fibrocytes)
A2A, A3 Ratf Ion recycling [135]
P2X2 Rate,f Ion recycling [100,184]
Outer sulcus epithelial cells (Bottchers and Claudius cells)
P2X2 Rate,f Paracellular ion recycling [100,184]
P2X2 Mousef Ion homeostasis [187]
P2X2 Gerbilc Activates nonselective cation channels to shunt K+ from endolymph [188]
P2Y4 Ratc Ion homeostasis [189]
Organ of Corti
Inner and outer hair cells
P2X2 Guinea-pigc,f,g Functionally localized to the apical surface; protection against acoustic
overstimulation
[93,110,112]
P2X2 Rate,f K+ shunt, cell deploarization and micromechanics [99,100,113,184]
P2X2 Mousef K+ shunt, cell deploarization and micromechanics [187]
P2X7 Ratf Function unknown [98]
P2Y1, P2Y2, P2Y4 Guinea-pigb,c,f PLC; Ins(1,4,5)P3; Ca
2+ signaling affects transduction [114,115]
A1, A2A, A3 Ratf Anti-oxidant stress response [135]
Supporting cells (Deiters cell, Hensens cells, pillar cells, inner phalangeal cells)
A1, A2A, A3 Ratf Otoprotective against ROS [135]
P2 Guinea-pigc Regulates micromechanics [118]
P2X2 Rate,f Micromechanics [100,184]
P2X2 Mousef Micromechanics [187]
P2X7 Ratf Micromechanics [98]
P2Y Rat PLC; Ins(1,4,5)P3; injury signal through JNK; ERK1/2 signaling
P2Y4 Guinea-pigf Might indicate paracrine ATP release and Ca2+ signaling [190]
Inner sulcus
P2X2 Rate,f Affects K+ shunt and ion homeostasis [100,184]
Interdental cells of the spiral limbusP2X2 Rat
e,f Possible role in ion homeostasis [100,184]
Spiral limbus fibrocytes
P2X1 Rate,f Transient down-regulated by P10 [183]
P2X2 Rate,f Ion homeostasis [100,184]
Spiral ganglion neurons
A1, A2A, A3 Ratf Protection from ROS [135]
P2X1, P2X2, P2X3, P2X4,
P2X5, P2X6, P2X7
Ratc,d,f,h P2X2 and P2X7 sustained; P2X2/P2X3 early postnatal [98,99,122,125,
183,191193]
P2Y Guinea-pigd PLC; Ins(1,4,5)P3 [96,192]
P2Y Ratc Regulates neuron excitability [97]
Olivocochlear efferent fibers (bundle)
P2X1 Rate,f Transient downregulation by P10 [183]
P2X7 Ratf Presynaptic; regulates ACh release [98]
Mesenchymal cells
P2X1 Rate,f Transiently expressed during development; downregulated by P10 [183]
aAbbreviations: Ach,acetylcholine;ERK, extracellular signal-regulated kinase;JNK, c-Jun N-terminal kinase; P10,postnatal day10; PKC,protein kinase C; PLC,phospholipaseC; ROS, reactive oxygen species.
Expression of purinergic receptors was identified by the following methods: bCa2+ imaging; celectrophysiology; dradioligand labeling; ein-situhybridization; fimmunohis-
tochemistry; gelectron microscopy; hRTPCR; ireceptor knockout.jHousley, G.D. et al. (2008) ATP-mediated humoral inhibition ofsound transduction supplants neural efferent inhibitionat high sound levels as the mechanismfor expanding
the dynamic range of hearing [abstract]. Assoc. Res. Otolaryngol. Abstract 623 (www.aro.org/archives/2008/2008_623_bf2a42ab.html ).
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partment during the stress of noise or hypoxia, including
release from vesiculated stores in the stria vascularis
[102,103] and release from the organ of Corti [104], would
activate the P2X2 receptors and produce a shunt conduc-
tance. This shunt has been demonstrated as a reduction
in the cochlear partition resistance in the guinea-pig
when ATP is injected into the endolymph [105]. This
causes a reversible reduction in EP. The ATP signal is
terminated by ecto-nucleotidase activity [106]. Comple-menting this P2X-receptor-mediated shunt of K+ (and
other minor cations) out of the scala media, the electro-
chemical driving force for sound transduction is also
decreased by P2Y4 receptorPLCprotein kinase C
(PKC)-mediated inhibition of the KCNE1/KCNQ1 chan-
nels, which provide the K+-influx pathway from the stria
vascularis [107,108].
Outer hair cells have a keyrole in sound transduction via
their electromotility, a unique property that enhances hear-
ing sensitivity and frequency selectivity[109]. Extracellular
ATP acts at nanomolar levels [110] to affect the non-linear
capacitance of the electromotility via P2Y receptor sig-
naling. At micromolar ATP levels, P2X2-receptor-gatedinward current would alter the electromotility by depolar-
izing the cells and by osmotically induced changes in cell
volume [111]. The hair-cell P2X-receptor-mediated shunt is
adaptive to noise stress. Very high densities of P2X2 recep-
tors are present on the stereocilia and cuticular plates of the
hair cells, but not the basolateral surface [93,112]. Intherat
model, after 72 h of 90 dB broadband noise, the ATP-gated
inward current in outer hair cells increased more than
threefold, which correlated with enhanced P2X2 immuno-
labelling on the stereocilia [113]. There was also an upre-
gulation in P2X2 transcript expression in the surrounding
cochlear partition epithelium, detected at 6 hours of sus-
tained noise exposure onwards.
Sound transduction in outer hair cells might also be
affected by P2Y-receptor-mediated Ca2+ signaling. P2Y2immunolabeling localizes to the apical region of the
guinea-pig outer hair cells [114]. Hensens body, an
Ins(1,4,5)P3-receptor-gated Ca2+ store under the cuticular
plate, is activated by this P2Y receptor signaling via liber-
ation of a G protein in the hair bundle, and the localized
elevation in Ca2+ probably alters actin binding, affecting
stereocilia stiffness [115]. P2-receptor-mediated Ca2+ sig-
naling within Deiters cells, originating in the apical pha-
langeal processthat projects to the reticular lamina between
the outer hair-cell cuticular plates, causes changes in the
stiffness of the cells that would affect transduction [116
118].Overall, purinergic signaling in the cochlear partition
can be viewed as a protective adaptation mechanism. As
the sound level rises, elevation of ATP from a low nano-
molar concentration [103,119] would activate the puriner-
gic signaling pathways, desensitize the transduction and
transmission processes and thereby extend the safe range
for hearing from the level where the neural efferent inhi-
bition of the outer hair cells saturates [120].
Cochlear development
During development, both type I and type II spiral
ganglion neurons undertake promiscuous innervation of
inner and outer hair cells. This is followed by programmed
pruning of mis-matched fibers, with the type I spiral
ganglion neurons withdrawing from the outer hair cells
and the type II fibers withdrawing from the inner hair
cells. This neural re-organization occurs within a few days
after birth in rodents, just before the onset of hearing. The
outgrowth and branching of the spiral ganglion neurites is
supported by neurotrophins secreted by the hair cells,
particularly brain-derived neurotrophic factor (BDNF)and neurotrophin 3 via TrkB and TrkC receptor tyrosine
kinase signaling, respectively [121]. P2X receptor sig-
naling contributes to the uncoupling of this neurotrophic
support. This is mediated by the transient expression of a
novel P2X2P2X3 heteromeric receptor, incorporating an
uncommon (P2X2-3) splice variant [122125] that exhibits
nanomolar ATP sensitivity. Activation of this receptor
blocks the BDNF-dependent outgrowth of the neurites
[125].
Extracellular nucleotide signaling also underlies the
induction of neurotransmission in the newly established
innervation of the inner hair cells. Paracrine ATP sig-
naling is central to this process. The neonatal cochlea isstructurally distinct in having a transient epithelium (the
Kollikers organ) medial to the inner hair cells. The Kolli-
kers organ epithelial cells spontaneously secrete ATP in
rhythmical bursts that activate P2 receptors on the inner
hair cells [126]. This, in turn, elicits synchronized release of
neurotransmitter from the inner hair cells, which activates
the type I spiral ganglion neurons. The effect involves ATP-
induced ATP release and can be blocked by treating the
tissue with apyrase, which hydrolyses endogenous ATP.
The purinergic receptors involved in this process, and the
pathway for release of ATP, have not been characterized at
a molecular level but involve both P2X and P2Y receptors
causing ATP release via connexin hemichannels in Kolli-
kers organ. ATP diffuses to the inner hair cells, where
inward currents, consistent with activation of P2X recep-
tors, lead to Ca2+ influx and pulsatile release of glutamate
at the ribbon synapses with the spiral ganglion neurites.
Rhythmic firing in the cochlear nerve ceases around the
time that the auditory canal opens in rodents ($P11), and
sound-conduction-induced activity commences. This ATP-
mediated activation of cochlear primary-afferent firing is
associated with the maturation of the central auditory
pathways, particularly the cochlear nuclei, and probably
consolidates the central synaptic mapping of cochlear
tonotopy [127].
Cochlear pathophysiologyATP release in the supporting cells of the organ of Corti
and spiral ligament is mediated via connexin [110] and
probably also pannexin 1 hemichannels [128]. Gap junc-
tions, particularly heteromers of Cx26 and Cx30, form the
conduit for ionic recirculation between the perilymph and
endolymph in response to the standing flux through the
hair cells [129,130]. Disruption of this conduit leads to
pathological changes in structure and function, which
might arise, in part, from theblock of purinergic signaling.
Ca2+ signaling between gap-junction-coupled cells
involves Cx and Px hemichannel-mediated ATP release,
which, with positive feedback, actsupon P2Y2 and/or P2Y4
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receptors to promote further Ins(1,4,5)P3 production via
the GqPLCbIns(1,4,5)P3 pathway and Ca2+ release
[131]. Rapid propagation of the Ca2+ signal occurs as
ATP diffuses to adjacent cells. The propagation of Ca2+
waves can be blocked by apyrase [132], as shown for the
ATP release in Kollikers organ during development [126].
This extracellular ATP-dependent Ca2+-signaling mech-
anism can be invoked by thedeath of a singlehaircell [132]
and might reflect a cochlear tissue-injury response. Theoscillatory Ca2+ waves in the organ of Corti supporting
cells and outer sulcus evoke a variety of spatiotemporal
injury responses in the tissue, including activating mem-
bers of the mitogen-activated protein kinase pathway,
including c-Jun N-terminal kinase (JNK) activity and
extracellularly regulated kinases 1 and 2 (ERK1/2)
[132,133], leading to hair-cell encroachment and scarring
of the reticular lamina.
Adenosine is otoprotective. In the cochlea, it can be
released from cells by bidirectional equilibrative and con-
centrative adenosine transporters [134] and by sequential
nucleotide hydrolysis via ectoNTPDases and 5-ecto-nucleo-
tidase activity, to be available to activate the four adeno-sine receptor subtypes [135]. In an acoustic
overstimulation model in gerbils, A1 receptor upregulation
was induced by reactive oxygen species (ROS) and nuclear
factor kB signaling[136]. Adenosine A1 receptor agonists
increase cochlear glutathione peroxidase and superoxide
dismutase expression that confers protection against ROS-
mediated ototoxicity arising from platinum-based che-
motherapy agents [137139].
Conclusions
Summarizing the data, there is considerable commonal-
ity among the different senses. In all cases, stimulus
transduction and information processing are modulated
by purinergic signaling. Moreover, the crosstalk between
neurons and supporting cells such as glial cells, retinal
pigment epithelial cells and sustentacular cells, in
addition to the signaling between the supporting cells,
involves purinergic pathways. Finally, the control of
progenitor proliferation and other developmental events,
in addition to the regulation of basal and glial cell
proliferation to protect and regenerate the damaged
tissues, seem to involve purinergic signaling. These sim-
ilarities are often reflected in particular subtypes of
purinergic receptors. For instance, P2Y1 and P2Y2 recep-
tors are characteristic for pathways to and among sup-
porting and glial cells, whereas P2X2 (or P2X2/3) and
P2X7 receptors frequently occur on sensory neurons.Currently, little is known about P1 adenosine receptors
in smell and taste, but, within the retina and inner ear,
A1 and A2 receptor action complements P2 signaling in
homeostatic roles. Usually, however, the previously men-
tioned rules of purinergic signaling are characteristic
not only for the sensory organs but also for other parts of
the central and peripheral nervous systems [2]. Thus, the
present state of our knowledge supports the conclusion
that purinergic signaling in a given part of the nervous
system is neither primarily determined by its ontogenetic
origin (i.e. from neural plate versus neural crest) nor by
any adaptation to specific tasks in information processing
(e.g. to different adequate stimuli). Rather, the puriner-
gic system seems to be a phylogenetically old and rather
universally usable and versatile tool to control the de-
velopment and diverse cellular interactions of the
vertebrate nervous system and fine-tune information
processing within it.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (RE8 4 9 /1 2 ; G RK 1 0 9 7/1 ; www.dfg.de/en) g ra nt s t o A .R ., b y t h e
Bundesministerium fur Bildung und Forschung (DLR/01GZ0703;
www.bmbf.de) grant to A.R., by the Interdisziplinares Zentrum fur
Klinische Forschung (www.izkf-leipzig.de) at the Faculty of Medicine of
the University of Leipzig (C35, Z10) grant to A.B., and by National
Health and Medical Research Council, Australia (www.nhmrc.gov.au),
Health Research Council, New Zealand (www.hrc.govt.nz) and Marsden
Fund (Royal Society of New Zealand; www.marsden.rsnz.org) grants to
G . D. H . G r ap h ic c o nt r ib u ti o ns b y J e ns G r os c h e i s g r at e fu l ly
acknowledged.
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