Evolutionary changes in the pharmacology of the nicotinic a9a10 receptor?

MOGLIE M; LIPOVSEK M; ELGOYHEN AB

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2012

Evolutionary changes in the pharmacology of the nicotinic a9a10 receptor The á9á10 nicotinic acetylcholine receptor (nAChR) mediates efferent inhibition of vertebrate hair cells. A phylogenetic analysis showed signatures of positive selection exclusively in the á10 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 á9á10 receptors and resemble those on rat á9. Most importantly, choline showed higher efficacy on chicken á9á10 receptors (88±8% max response to ACh, n=4) compared to rat á9á10 receptors (34±4% max response to ACh, n=4). Moreover, in a Ratá9Chická10 hybrid receptor, responses to choline were 88±7% (n=X) of the maximal response to ACh, resembling chicken receptors and strongly suggesting that the sites involved have been altered in mammalian á10 subunits. We conclude 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 on mammalian á10 subunits.