Functional consequences of adaptive evolution of the mammalian a9a10 nicotinic receptor

M. LIPOVSEK; L. F. FRANCHINI; E. KATZ; N. MILLAR; P. A. FUCHS; A. B. ELGOYHEN

Chicago, Illinois, USA.

Simposio; Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science. Satellite event of the Annual Meeting of the Society for Neuroscience; 2009

Society for Neuroscience

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 oocyte’s endogenous calcium dependent chloride current stimulated by rat a9a10 was not activated by the G. gallus a9a10 receptors, suggesting that 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.