Receptor nicotínico de células ciliadas auditivas: de estructura a función

ELGOYHEN AB

Cordoba

Simposio; XXXVIII Congreso de la SAFE; 2006

Nicotinic Receptors of Cochlear Hair cells: from structure to function Ana Belén Elgoyhen, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET), 3ra Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires. Vuelta de Obligado 2490, Buenos Aires 1428, elgoyhen@dna.uba.ar   Acetylcholine (ACh) is the principal neurotransmitter released by medial olivocochlear efferent axons, and existing data suggest a central role for an atypical nicotinic cholinergic receptor (nAChR) located at the synapse between efferent fibers and vertebrate outer hair cells. Current data support a model in which ACh-gated depolarization is followed by activation of small-conductance, calcium-activated potassium channel (SK2) and subsequent hair cell hyperpolarization. We have been able to define the molecular structure of the mammalian hair cell nAChR, and have demonstrated that it is assembled from a9 and a10 nAChR subunits, in a 2:3 stoichiometry. Although homomeric a9 receptors are functional, the a10 subunit serves as a structural component leading to heteromeric a9a10 nAChRs with particular desensitization kinetics, current-voltage dependency and sensitivity to extracellular Ca2+. Moreover, we have demonstrated that recombinant a9a10 nAChR and native mammalian hair cell receptors share similar pharmacological and biophysical properties. Although a9 and a10 are the latest vertebrate nAChR subunits that have been cloned, their identification has established a distant early divergent branch within the nAChR gene family, most closely related to the ancestor that gave origin to the family. During my talk I will provide the experimental evidence, derived from molecular and cellular biology, physiology and gene targeting approaches, which led to the description of the functional role/s of a9 and a9a10 nAChRs.