Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells

ZORRILLA DE SAN MARTIN, J; BALLESTERO, J; KATZ, E; ELGOYHEN, AB; FUCHS, PA

Denver, USA

Congreso; 30th Midwinter Meeting, Association for Research in Otolaryngology; 2007

Associtation for Research in Otolaryngology

The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include ‘ryanodine receptors’ whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells is confounded by the unusual pharmacology of the á9á10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine is a positive modulator of the a9a10 nAChR expressed in Xenopus oocytes, the first such compound to be found and corresponds to an increase in the apparent affinity and efficacy for acetylcholine (ACh). Moreover, ACh-evoked currents through the isolated cholinergic receptor of inner hair cells (IHCs) in excised mouse cochleas were enhanced ~ 50% by 200 µM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation is not unique to the mammalian receptor. The response of chicken hair cells exposed to ACh likewise was enhanced in the presence of 100 µM ryanodine. This facilitatory effect on current through the AChR also could result in greater activation of associated calcium-dependent K+ (SK) channels in hair cells under conditions that permitted this activity. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate a9a10 mediated responses and for potential inner ear therapeutics based on this interaction.