FUNCTIONAL CONSEQUENCES OF ADAPTIVE EVOLUTION OF

LIPOVSEK M; FRANCHINI L; KATZ E; FUCHS PA; ELGOYHEN AB

Bahía Blanca

Workshop; Workshop of the Sociedad Argentina de Investigación en Neurociencias, Neuronal Communication: From structure to physiology; 2008

Sociedad Argentina de Investigación en Neurociencias,

FUNCTIONAL CONSEQUENCES OF ADAPTIVE EVOLUTION OF THE MAMMALIAN a9a10 NICOTINIC RECEPTOR. M. Lipovsek1, L. F. Franchini1, E. Katz1, P. A. Fuchs2 and A. B. Elgoyhen1. 1 INGEBI – CONICET. Buenos Aires, Argentina. 2 Johns Hopkins University School of Medicine Baltimore, MD, USA. The a9a10 nicotinic acetylcholine receptor (nAChR) mediates efferent inhibition of cochlear hair cells in mammals and birds. This inhibition results from activation of a calcium-dependent potassium current thought to depend on calcium entry through the activated nAChR. Sequence analysis of the CHRNA10 genes (but not of CHRNA9) of different species revealed signs of adaptive evolution in the mammalian lineage (Franchini and Elgoyhen, 2006). Therefore, one could propose that the mammalian a9a10 receptor (i.e., from R. norvegicus) would have functional properties different from those of the avian receptor (i.e., from G. gallus) as a result of specific, non-synonymous substitutions within the CHRNA10 gene. To begin to test this hypothesis, we analyzed the properties of the recombinant chicken a9a10 receptor, using the two-electrode voltage-clamp technique in Xenopus laevis oocytes expressing these subunits. The sensitivity to ACh of the G. gallus receptor was lower than that of the R. norvegicus receptor (EC50=21.7±1.2mM and 13.8±1.7mM, respectively). In addition, the G. gallus a9a10 receptor did not desensitize significantly, in a manner similar to that of the homomeric a9 from rat, and different to the strong desensitization of the heteromeric a9a10 R. norvegicus receptor. Perhaps most notably, the calcium permeability of the avian receptor is substantially lower than that of the mammalian receptor. These results indicate that the mammalian a9a10 receptor has acquired new functional properties which are different from those of non-mammalian species. This most likely results from the positive selection of non-synonymous substitutions in the a10 subunit during the evolution of this lineage. Supported by NIH, HHMI, UBA and ANPCyT.