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

MOGLIE, MARCELO J.; MARCOVICH, IRINA; CORRADI, JEREMÍAS; CARPANETO FREIXAS, AGUSTÍN E.; GALLINO, SOFÍA; PLAZAS, PAOLA V.; BOUZAT, CECILIA; LIPOVSEK, MARCELA; ELGOYHEN, ANA BELÉN

Frontiers in Molecular Neuroscience

Frontiers

Año: 2021 vol. 14

The a9a10 nicotinic acetylcholine receptor (nAChR) plays a fundamental role in innerear physiology. It mediates synaptic transmission between efferent olivocochlear fibersthat descend from the brainstem and hair cells of the auditory sensory epithelium.The a9 and a10 subunits have undergone a distinct evolutionary history within thefamily of nAChRs. Predominantly in mammalian vertebrates, the a9a10 receptor hasaccumulated changes at the protein level that may ultimately relate to the evolutionaryhistory of the mammalian hearing organ. In the present work, we investigated theresponses of a9a10 nAChRs to choline, the metabolite of acetylcholine degradation atthe synaptic cleft. Whereas choline is a full agonist of chicken a9a10 receptors it is apartial agonist of the rat receptor. Making use of the expression of a9a10 heterologousreceptors, encompassing wild-type, heteromeric, homomeric, mutant, chimeric, andhybrid receptors, and in silico molecular docking, we establish that the mammalian(rat) a10 nAChR subunit underscores the reduced efficacy of choline. Moreover,we show that whereas the complementary face of the a10 subunit does not playan important role in the activation of the receptor by ACh, it is strictly requiredfor choline responses. Thus, we propose that the evolutionary changes acquiredin the mammalian a9a10 nAChR resulted in the loss of choline acting as a fullagonist at the efferent synapse, without affecting the triggering of ACh responses.This may have accompanied the fine-tuning of hair cell post-synaptic responses tothe high-frequency activity of efferent medial olivocochlear fibers that modulate thecochlear amplifier.