Pharmacological consequences of adaptive evolution of the alpha9alpha10 nAChR.?

MARCELO MOGLIE; MARCELA LIPOVSEK; HOWARD MOSKOWITZ; PAUL ALBERT FUCHS; ANA BELÉN ELGOYHEN

Huerta Grande, Córdoba

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

Sociedad Argentina de Investigación en Neurociencia

The α9 and α10 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 α10 subunits (Franchini & Elgoyhen, 2006). Here, we assayed the functional consequences of the acquisition of non-synonymous substitutions in 10 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 α9α10 receptors (Ch:88±6%;n=6, DMPP:32±3%;n=5) compared to rat α9α10 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 Ch is mainly determined by α10 subunits (Rα9Cα10: 87±3%; n=5, Cα9Rα10: 57±4%; n=2). Taken together, these results suggest that the aminoacid changes that accumulated on mammalian α10 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 α10 subunits.