Promiscuous coassembly of serotonin 5-HT 3 and nicotinic α4 receptor subunits into Ca 2+ -permeable ion channels

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Abstract
Serotonin (5-hydroxytryptamine) type 3 receptors (5-HT3R) and nicotinic acetylcholine receptors are structurally and functionally related proteins, yet distinct members of the family of ligand-gated ion channels. For most members of this family a diversity of heteromeric receptors is known at present. In contrast, known 5-HT3R subunits are all homologs of the same 5-HT3R-A subunit and form homopentameric receptors. Here we show, by heterologous expression followed by immunoprecipitation, that 5-HT3R and nicotinic acetylcholine receptor α4 subunits coassemble into a novel type of heteromeric ligand-gated ion channel, which is activated by 5-HT. The Ca2+ permeability of this heteromeric ion channel is enhanced as compared with that of the homomeric 5-HT3R channel. Heteromeric 5-HT3/α4 and homomeric 5-HT3Rs have similar pharmacological profiles, but distinct sensitivities to block by the antagonist d-tubocurarine. Coassembly of subunits beyond the boundaries of ligand-gated ion channel families may constitute an important mechanism contributing to the diverse properties and functions of native neurotransmitter receptors.