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β3 Subunits Promote Expression and Nicotine-Induced Up-Regulation of Human Nicotinic 6^* Nicotinic Acetylcholine Receptors Expressed in Transfected Cell Lines

Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania

Nicotinic acetylcholine receptors (AChRs) containing 6 subunits are typically found at aminergic nerve endings where they play important roles in nicotine addiction and Parkinson's disease. 6^* AChRs usually contain β3 subunits. β3 subunits are presumed to assemble only in the accessory subunit position within AChRs where they do not participate in forming acetylcholine binding sites. Assembly of subunits in the accessory position may be a critical final step in assembly of mature AChRs. Human 6 AChRs subtypes were permanently transfected into human tsA201 human embryonic kidney (HEK) cell lines. 6β2β3 and 6β4β3 cell lines were found to express much larger amounts of AChRs and were more sensitive to nicotine-induced increase in the amount of AChRs than were 6β2 or 6β4 cell lines. The increased sensitivity to nicotine-induced up-regulation was due not to a β3-induced increase in affinity for nicotine but probably to a direct effect on assembly of AChR subunits. HEK cells express only a small amount of mature 6β2 AChRs, but many of these subunits are on the cell surface. This contrasts with Xenopus laevis oocytes, which express a large amount of incorrectly assembled 6β2 subunits that bind cholinergic ligands but form large amorphous intracellular aggregates. Monoclonal antibodies (mAbs) were made to the 6 and β3 subunits to aid in the characterization of these AChRs. The 6 mAbs bind to epitopes C-terminal of the extracellular domain. These data demonstrate that both cell type and the accessory subunit β3 can play important roles in 6^* AChR expression, stability, and up-regulation by nicotine.

Address correspondence to: Dr. Jon Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104. E-mail: jslkk{at}mail.med.upenn.edu

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