Promiscuous coassembly of serotonin 5-HT3 and nicotinic alpha4 receptor subunits into Ca(2+)-permeable ion channels.
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 alpha4 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/alpha4 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.
van Hooft
J A
JA
Research Institute of Toxicology, Utrecht University, P.O. Box 80. 176, NL-3508 TD Utrecht, The Netherlands.
Spier
A D
AD
Yakel
J L
JL
Lummis
S C
SC
Vijverberg
H P
HP
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D016257:Fura-2 / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008845:Microinjections; D009865:Oocytes / Q000378:metabolism*; D011233:Precipitin Tests; D011487:Protein Conformation; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D014403:Tubocurarine / Q000494:pharmacology; D014981:Xenopus
D015220:Calcium Channels; D018076:DNA, Complementary; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D002118:Calcium; D016257:Fura-2; D014403:Tubocurarine