Pharmacological consequences of adaptive evolution of the alpha9alpha10 nAChR.?

MOGLIE M; LIPOVSEK M; MOSKOWITZ H; FUCHS PA; ELGOYHEN AB

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2013

Sociedad Argentina de Investigación en Neurociencia

The á9 and á10 nicotinic acetylcholine receptor (nAChR) subunits form the receptor that mediates efferent inhibition of vertebrate cochlear hair cells. A phylogenetic analysis of the genes coding for each subunit showed signatures of positive selection only for the mammalian á10 subunits (Franchini & Elgoyhen, 2006 ). Here, we assayed the functional consequences of the acquisition of non-synonymous substitutions in a10, by comparing the pharmacology of recombinant chicken and rat receptors heterologuosly expressed in Xenopus Laevis oocytes. Cholinergic agonists such as Choline (Ch) and DMPP showed higher efficacy on chicken á9á10 receptors (Ch:88±6%;n=6, DMPP:32±3%;n=5) compared to rat á9á10 nAChRs (Ch:37±2%;n=10, DMPP:0,6±0,3%;n=6). Moreover, responses to Ch were 72±3% (n=3) of the maximal response to ACh in chicken hair cells chicken. Finally, the heterologous expression of hybrid interspecies receptors revealed that the efficacy of choline is mainly determined by á10 subunits (Rá9Cá10: 87±3%;n=5, Cá9Rá10: 57±4%;n=2). Taken together, these results suggest that the aminoacid changes that accumulated on mammalian á10 subunits resulted in the pharmacological differences observed. Most importantly, we propose that the efficacy of choline (the main synaptic metabolite of ACh) to elicit a response may lay behind the selection pressure that shaped mammalian á10 subunits.