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6-Containing Nicotinic Acetylcholine Receptors Is Selectively Reduced, but Not Eliminated, by 
3 Subunit Gene Deletion
Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy (C.G., M.M., F.C., L.R.); Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (M.J.M., A.C.C., P.W.); and Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (J.M.M.)
mRNAs for the neuronal nicotinic acetylcholine receptor (nAChR) 
6 and 
3 subunits are abundantly expressed and colocalized in dopaminergic cells of the substantia nigra and ventral tegmental area. Studies using subunit-null mutant mice have shown that 6- or 3-dependent nAChRs bind -conotoxin MII (-CtxMII) with high affinity and modulate striatal dopamine release. This study explores the effects of 3 subunit-null mutation on striatal and midbrain nAChR expression, composition, and pharmacology. Ligand binding and immunoprecipitation experiments using subunit-specific antibodies indicated that 3-null mutation selectively reduced striatal 6* nAChR expression by 76% versus 3+/+ control. Parallel experiments showed a smaller reduction in both midbrain 3* and 6* nAChRs (34 and 42% versus 3+/+ control, respectively). Sedimentation coefficient determinations indicated that residual 6* nAChRs in 3–/– striatum were pentameric, like their wild-type counterparts. Immunoprecipitation experiments on immunopurified 3* nAChRs demonstrated that almost all wild-type striatal 3* nAChRs also contain 4, 6, and 2 subunits, although a small population of non-3 6* nAChRs is also expressed. 3 subunit incorporation seemed to increase 4 participation in 62* complexes. 125I-Epibatidine competition binding studies showed that the -CtxMII affinity of 6* nAChRs from the striata of 3–/– mice was similar to those isolated from 3+/+ animals. Together, the results of these experiments show that the 3 subunit is important for the correct assembly, stability and/or transport of 6* nAChRs in dopaminergic neurons and influences their subunit composition. However, 3 subunit expression is not essential for the expression of 6*, high-affinity -CtxMII binding nAChRs.
Address correspondence to: Dr. Cecilia Gotti, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Section of Cellular and Molecular Pharmacology Center, Department of Medical Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: c.gotti{at}in.cnr.it
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