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Received November 14, 2001
Accepted after revision January 15, 2002
7 and ß2 subunits co-assemble to form functional heteromeric nicotinic receptor channels
1 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709, USA
2 Department of Pharmacology, University College London, London WC1E 6BT, UK
3 NIEHS, F2-08, PO Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA
* To whom correspondence should be addressed. E-mail: yakel{at}niehs.nih.gov.
Rat hippocampal interneurons express diverse subtypes of functional nicotinic acetylcholine receptors (nAChRs), including 7-containing receptors that have properties unlike those expected for homomeric 7 nAChRs. We previously reported a strong correlation between expression of the 7 and of the ß2 subunits in individual neurons. To explore whether co-assembly of the 7 and ß2 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 ß2 subunit, both wild-type and mutant forms, with the 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 7 receptor channels, both carbachol and choline were only partial agonists in oocytes expressing both 7 and ß2 subunits. In addition the EC50 values for all three agonists significantly increased when the ß2 subunit was co-expressed with the 7 subunit. Co-expression with the ß2 subunit did not result in any significant change in the current-voltage curve. Biochemical evidence for the co-assembly of the 7 and ß2 subunits was obtained by co-immunoprecipitation of these subunits from transiently transfected human embryonic kidney (TSA120) cells. These data provide direct biophysical and molecular evidence that the nAChR 7 and ß2 subunits co-assemble to form a functional heteromeric nAChR with functional and pharmacological properties different from those of homomeric 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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