title: Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor.
abstract: The α9 and α10 cholinergic nicotinic receptor subunits assemble to form the receptor that mediates efferent inhibition of hair cell function within the auditory sensory organ, a mechanism thought to modulate the dynamic range of hearing. In contrast to all nicotinic receptors, which serve excitatory neurotransmission, the activation of α9α10 produces hyperpolarization of hair cells. An evolutionary analysis has shown that the α10 subunit exhibits signatures of positive selection only along the mammalian lineage, strongly suggesting the acquisition of a unique function. To establish whether mammalian α9α10 receptors have acquired distinct functional properties as a consequence of this evolutionary pressure, we compared the properties of rat and chicken recombinant and native α9α10 receptors. Our main finding in the present work is that, in contrast to the high (pCa(2+)/pMonovalents ∼10) Ca(2+) permeability reported for rat α9α10 receptors, recombinant and native chicken α9α10 receptors have a much lower permeability (∼2) to this cation, comparable to that of neuronal α4β2 receptors. Moreover, we show that, in contrast to α10, α7 as well as α4 and β2 nicotinic subunits are under purifying selection in vertebrates, consistent with the conserved Ca(2+) permeability reported across species. These results have important consequences for the activation of signaling cascades that lead to hyperpolarization of hair cells after α9α10 gating at the cholinergic-hair cell synapse. In addition, they suggest that high Ca(2+) permeability of the α9α10 cholinergic nicotinic receptor might have evolved together with other features that have given the mammalian ear an expanded high-frequency sensitivity.
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular,  Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires,  Argentina.
authors.forename: Marcela
authors.initials: M
authors.lastname: Lipovsek
authors.forename: Gi Jung
authors.initials: GJ
authors.lastname: Im
authors.forename: Lucía F
authors.initials: LF
authors.lastname: Franchini
authors.forename: Francisco
authors.initials: F
authors.lastname: Pisciottano
authors.forename: Eleonora
authors.initials: E
authors.lastname: Katz
authors.forename: Paul Albert
authors.initials: PA
authors.lastname: Fuchs
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Elgoyhen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics*; D002645:Chickens; D019143:Evolution, Molecular; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016013:Likelihood Functions; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010802:Phylogeny; D021122:Protein Subunits / Q000235:genetics; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D000109:Acetylcholine; D002118:Calcium