Rat nicotinic ACh receptor alpha7 and beta2 subunits co-assemble to form functional heteromeric nicotinic receptor channels

doi:10.1113/jphysiol.2001.013847

Rat nicotinic ACh receptor $alpha$ 7 and $beta$ 2 subunits co-assemble to form functional heteromeric nicotinic receptor channels

Serguei S. Khiroug, Patricia C. Harkness, Patricia W. Lamb, Sterling N. Sudweeks, Leonard Khiroug, Neil S. Millar and Jerrel L. Yakel

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709, USA and *Department of Pharmacology, University College London, London WC1E 6BT, UK

Rat hippocampal interneurons express diverse subtypes of functional nicotinic acetylcholine receptors (nAChRs), including $alpha$ 7-containing receptors that have properties unlike those expected for homomeric $alpha$ 7 nAChRs. We previously reported a strong correlation between expression of the $alpha$ 7 and of the $beta$ 2 subunits in individual neurons. To explore whether co-assembly of the $alpha$ 7 and $beta$ 2 subunits might occur, these subunits were co-expressed in Xenopus oocytes and the functional properties of heterologously expressed nAChRs were characterized by two-electrode voltage clamp. Co-expression of the $beta$ 2 subunit, both wild-type and mutant forms, with the $alpha$ 7 subunit significantly slowed the rate of nAChR desensitization and altered the pharmacological properties. Whereas ACh, carbachol and choline were full or near-full agonists for homomeric $alpha$ 7 receptor channels, both carbachol and choline were only partial agonists in oocytes expressing both $alpha$ 7 and $beta$ 2 subunits. In addition the EC₅₀ values for all three agonists significantly increased when the $beta$ 2 subunit was co-expressed with the $alpha$ 7 subunit. Co-expression with the $beta$ 2 subunit did not result in any significant change in the current-voltage curve. Biochemical evidence for the co-assembly of the $alpha$ 7 and $beta$ 2 subunits was obtained by co-immunoprecipitation of these subunits from transiently transfected human embryonic kidney (TSA201) cells. These data provide direct biophysical and molecular evidence that the nAChR $alpha$ 7 and $beta$ 2 subunits co-assemble to form a functional heteromeric nAChR with functional and pharmacological properties different from those of homomeric $alpha$ 7 channels. This co-assembly may help to explain nAChR channel diversity in rat hippocampal interneurons, and perhaps in other areas of the nervous system.

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