King's College London

TY - JOUR

T1 - Loss of Choline Agonism in the Inner Ear Hair Cell Nicotinic Acetylcholine Receptor Linked to the α10 Subunit

AU - Moglie, Marcelo J.

AU - Marcovich, Irina

AU - Corradi, Jeremías

AU - Carpaneto Freixas, Agustín E.

AU - Gallino, Sofía

AU - Plazas, Paola V.

AU - Bouzat, Cecilia

AU - Lipovsek, Marcela

AU - Elgoyhen, Ana Belén

N1 - Funding Information: We thank Paul A. Fuchs for assistance in the performance of chicken hair cell recordings. Funding. This work was supported by Agencia Nacional de Promoci?n Cient?ficas y T?cnicas, Argentina, the Scientific Grand Prize of the Fondation Pour l?Audition, and NIH grant R01 DC001508 (Paul Fuchs PI and ABE co-PI) to ABE. Funding Information: This work was supported by Agencia Nacional de Promoción Científicas y Técnicas, Argentina, the Scientific Grand Prize of the Fondation Pour l’Audition, and NIH grant R01 DC001508 (Paul Fuchs PI and ABE co-PI) to ABE. Publisher Copyright: © Copyright © 2021 Moglie, Marcovich, Corradi, Carpaneto Freixas, Gallino, Plazas, Bouzat, Lipovsek and Elgoyhen. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2/5

Y1 - 2021/2/5

N2 - The α9α10 nicotinic acetylcholine receptor (nAChR) plays a fundamental role in inner ear physiology. It mediates synaptic transmission between efferent olivocochlear fibers that descend from the brainstem and hair cells of the auditory sensory epithelium. The α9 and α10 subunits have undergone a distinct evolutionary history within the family of nAChRs. Predominantly in mammalian vertebrates, the α9α10 receptor has accumulated changes at the protein level that may ultimately relate to the evolutionary history of the mammalian hearing organ. In the present work, we investigated the responses of α9α10 nAChRs to choline, the metabolite of acetylcholine degradation at the synaptic cleft. Whereas choline is a full agonist of chicken α9α10 receptors it is a partial agonist of the rat receptor. Making use of the expression of α9α10 heterologous receptors, encompassing wild-type, heteromeric, homomeric, mutant, chimeric, and hybrid receptors, and in silico molecular docking, we establish that the mammalian (rat) α10 nAChR subunit underscores the reduced efficacy of choline. Moreover, we show that whereas the complementary face of the α10 subunit does not play an important role in the activation of the receptor by ACh, it is strictly required for choline responses. Thus, we propose that the evolutionary changes acquired in the mammalian α9α10 nAChR resulted in the loss of choline acting as a full agonist at the efferent synapse, without affecting the triggering of ACh responses. This may have accompanied the fine-tuning of hair cell post-synaptic responses to the high-frequency activity of efferent medial olivocochlear fibers that modulate the cochlear amplifier.

AB - The α9α10 nicotinic acetylcholine receptor (nAChR) plays a fundamental role in inner ear physiology. It mediates synaptic transmission between efferent olivocochlear fibers that descend from the brainstem and hair cells of the auditory sensory epithelium. The α9 and α10 subunits have undergone a distinct evolutionary history within the family of nAChRs. Predominantly in mammalian vertebrates, the α9α10 receptor has accumulated changes at the protein level that may ultimately relate to the evolutionary history of the mammalian hearing organ. In the present work, we investigated the responses of α9α10 nAChRs to choline, the metabolite of acetylcholine degradation at the synaptic cleft. Whereas choline is a full agonist of chicken α9α10 receptors it is a partial agonist of the rat receptor. Making use of the expression of α9α10 heterologous receptors, encompassing wild-type, heteromeric, homomeric, mutant, chimeric, and hybrid receptors, and in silico molecular docking, we establish that the mammalian (rat) α10 nAChR subunit underscores the reduced efficacy of choline. Moreover, we show that whereas the complementary face of the α10 subunit does not play an important role in the activation of the receptor by ACh, it is strictly required for choline responses. Thus, we propose that the evolutionary changes acquired in the mammalian α9α10 nAChR resulted in the loss of choline acting as a full agonist at the efferent synapse, without affecting the triggering of ACh responses. This may have accompanied the fine-tuning of hair cell post-synaptic responses to the high-frequency activity of efferent medial olivocochlear fibers that modulate the cochlear amplifier.

KW - acetylcholine

KW - choline

KW - cochlea

KW - evolution

KW - hearing

KW - ion channels

KW - nicotinic receptors

UR - http://www.scopus.com/inward/record.url?scp=85101215001&partnerID=8YFLogxK

U2 - 10.3389/fnmol.2021.639720

DO - 10.3389/fnmol.2021.639720

M3 - Article

AN - SCOPUS:85101215001

VL - 14

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

SN - 1662-5099

M1 - 639720

ER -