Evolutionary changes in the pharmacology of the nicotinic α9α10 receptor

MOGLIE M; LIPOVSEK M; ELGOYHEN AB

Huerta Grande, Córdoba

Congreso; XXVII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2012

Sociedad Argentina de Investigación en Neurociencias

Evolutionary changes in the pharmacology of the nicotinic alpha9alpha10 receptor Marcelo J. Moglie, Marcela Lipovsek, Ana Belén Elgoyhen Instituto de Investigaciones en Ingeniería Genética y Biología Molecular - INGEBI (CONICET) The α9α10 nicotinic acetylcholine receptor (nAChR) mediates efferent inhibition of vertebrate hair cells. A phylogenetic analysis showed signatures of positive selection exclusively in the α10 subunit within the mammalian lineage (Franchini& Elgoyhen, 2006). Here, we assayed the effects of these non-synonymous substitutions by comparing the pharmacology of recombinant chicken and rat receptors. We found that the effects of the agonists choline and DMPP and the antagonist serotonin on chicken receptors differ from those on rat α9α10 receptors and resemble those on rat α9. Above all, choline showed higher efficacy on chicken α9α10 receptors (88±8% max response to ACh, n=4) compared to rat α9α10 receptors (34±4% max response to ACh, n=4). Moreover, in a Ratα9Chickα10 hybrid receptor, responses to choline were 88±7% (n=2) of the maximal response to ACh, resembling chicken receptors and strongly suggesting that the sites involved have been altered in mammalian α10 subunits. We conclude 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 on mammalian α10 subunits.