EXTRACELLULAR NUCLEOTIDE SIGNALING IN THE INNER-EAR

Extracellular nucleotides, particularly adenosine 5'-triphosphate (ATP ), act as signaling molecules in the inner ear. Roles as neurotransmit ters, neuromodulators, and as autocrine or paracrine humoral factors a re evident. The diversity of the signaling pathways for nucleotides, w hich include a variety of ATP-gated ion channels (assembled from diffe rent subtypes of P2X-receptor subunit) and also different subtypes of G protein-coupled nucleotide receptors (P2Y receptors) supports a majo r physiological role for ATP in the regulation of hearing and balance. Almost invariably both P2X and P2Y receptor expression is apparent in the complex tissue structures associated with the inner-ear labyrinth . However P2X-receptor expression, commonly associated with fast neuro transmission, is apparent not only with the cochlear and vestibular pr imary afferent neurons, but also appears to mediate humoral signaling via Am-gated ion channel localization to the endolymphatic surface of the cochlear sensory epithelium (organ of Corti). This is the site of the sound-transduction process and recent data, including both electro physiological, imaging, and immunocytochemistry, has shown that the AT P-gated ion channels are colocalized here with the mechano-electrical transduction channels of the cochlear hair cells. In contrast to this direct action of extracellular ATP on the sound-transduction process, an indirect effect is apparent via P2Y-receptor expression, prevalent on the marginal cells of the stria vascularis, a tissue that generates the standing ionic and electrical gradients across the cochlear parti tion. The site of generation of these gradients, including the dark-ce ll epithelium of the vestibular labyrinth, may be under autocrine or p aracrine regulation mediated by P2Y receptors sensitive to both purine s (ATP) and pyrimidines such as UTP. There is also emerging evidence t hat the nucleoside adenosine, formed as a breakdown product of ATP by the action of ectonucleotidases and acting via P1 receptors, is also p hysiologically significant in the inner ear. P1-receptor expression (i ncluding A(1), A(2), and A(3) subtypes) appear to have roles associate d with stress, acting alongside P2Y receptors to enhance cochlear bloo d flow and to protect against the action of free radicals and to modul ate the activity of membrane conductances. Given the positioning of a diverse range of purinergic-signaling pathways within the inner ear, e levations of nucleotides and nucleosides are clearly positioned to aff ect hearing and balance. Recent data clearly supports endogenous ATP-a nd adenosine-mediated changes in sensory transduction via a regulation of the electrochemical gradients in the cochlea, alterations in the a ctive and passive mechanical properties of the cells of the sensory ep ithelium, effects on primary afferent neurons, and control of the bloo d supply. The field now awaits conclusive evidence linking a physiolog ically-induced modulation of extracellular nucleotide and nucleoside l evels to altered inner ear function.