Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products
Autor: | David S. Bredt, Jose A. Matta, Hae-Jin Kweon, Madhurima Dhara, Weston B. Davini, Daniel Knowland, Min Lei O'carroll, Shenyan Gu |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Deafness Receptors Nicotinic Ligands Synapse 03 medical and health sciences Mice 0302 clinical medicine Postsynaptic potential Hair Cells Auditory medicine otorhinolaryngologic diseases Animals Humans Cochlea Acetylcholine receptor Multidisciplinary Chemistry Membrane Proteins Biological Sciences Cell biology Nicotinic acetylcholine receptor 030104 developmental biology Nicotinic agonist medicine.anatomical_structure Synapses Cholinergic Hair cell sense organs 030217 neurology & neurosurgery Protein Binding |
Zdroj: | Proc Natl Acad Sci U S A |
ISSN: | 1091-6490 |
Popis: | Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10 nicotinic acetylcholine receptors (nAChRs), which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Here, genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Collectively, this study provides a mechanism to link cholinergic input with α9α10 assembly, identifies unexpected functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders. |
Databáze: | OpenAIRE |
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