Review
Purinergic signaling in special senses

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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 receptor signaling underpins the sensory transduction and information coding in these sense organs. The P2 and P1 receptors mediate fast transmission of sensory signals and have modulatory roles in the regulation of synaptic transmitter release, for example in the adaptation to sensory overstimulation. Purinergic signaling regulates bidirectional neuron–glia interactions and is involved in the control of blood supply, extracellular ion homeostasis and the turnover of sensory epithelia by modulating apoptosis and progenitor proliferation. Purinergic signaling is an important player in pathophysiological processes in sensory tissues, and has both detrimental (pro-apoptotic) and supportive (e.g. initiation of cytoprotective 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 system. 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 dinucleotides) 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 comprise at 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 receptors are involved in neuromodulation and neuron–glia 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 synaptic terminals, and from non-neuronal cells by secretion of vesicles or calcium-independent mechanisms via plasma-membrane nucleotide-transport proteins, connexin or pannexin hemichannels, anion channels and other processes [2]. Adenosine can be released by nucleoside transporters or is formed extracellularly from ATP by ecto-nucleotidases [2]. Degradation of nucleotides by ecto-nucleotidases also provides rapid termination of purinergic signaling [2].

As in the brain, purinergic receptors are abundant in the tissues of special senses. Here, we aim to critically evaluate what is presently known (and proposed) about the pathways 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 characteristics 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 systems provides an opportunity to consider which roles are adaptations to specific purposes and which are general features of the nervous tissue.

Section snippets

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 manner 3, 4 and from glial and pigment epithelial cells by Ca2+-independent mechanisms 5, 6, 7, 8. Adenosine might be released via nucleoside transporters by ganglion and glial cells [8], and it can be formed enzymatically in the extracellular space from ATP 9, 10, 11. Ecto-nucleotidases have been localized to both plexiform

Olfaction

The nose of vertebrates utilizes various systems for chemosensation including the main olfactory system, vomeronasal organ, Grüneberg ganglion and trigeminal system. The main olfactory epithelium consists of olfactory receptor 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 sympathetic and trigeminal nerve fibers 65, 66, 67 and from cells that are acutely injured by toxic

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 modalities and glia–sensory-cell communication. This occurs via a non-vesicular mechanism involving pannexin 1 [76] and connexin [77] hemichannels.

Hearing

The cochlea exhibits a diverse array of purinergic signaling components. This includes all seven ionotropic P2X receptor subunits and all studied metabotropic P2Y receptors, in addition to P1 receptor signaling via adenosine arising, in part, from conversion of nucleotides by ecto-nucleotidases. Figure 4 and Table 4 highlight important purinergic signaling mechanisms supporting the maintenance of sound transduction and neurotransmission in the cochlea.

Conclusions

Summarizing the data, there is considerable commonality 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

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (RE 849/12; GRK 1097/1; www.dfg.de/en) grants to A.R., by the Bundesministerium für Bildung und Forschung (DLR/01GZ0703; www.bmbf.de) grant to A.R., by the Interdisziplinäres Zentrum für 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/

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