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Novel G423S Mutation of Human 7 Nicotinic Receptor Promotes Agonist-Induced Desensitization by a Protein Kinase C-Dependent Mechanism

Departments of Clinical Pharmacology (H.T., S.K., K.T., S.K., T.W., I.K., T.S.) and Neuropsychiatry (M.T., T.M., M.K.), University of Toyama, Toyama, Japan; and Hokuriku National Hospital, Toyama, Japan (M.M.)

The 7 nicotinic acetylcholine receptor subunit (CHRNA7) gene harbors a high degree of polymorphism. In this study, we found a novel variant (1267 G to A) in exon 10 of the CHRNA7 gene in a Japanese population. This variant results in glycine-to-serine substitution at position 423 (G423S) located in the large cytoplasmic loop of the protein. To clarify the possibility that the G423S mutation alters the pharmacological properties of 7 receptors, acetylcholine (ACh)-elicited current through 7-G423S mutant receptors expressed in Xenopus laevis oocytes was measured using the two-electrode voltage-clamp technique. We found that the current elicited by ACh (1 mM, 5 s) through 7-G423S receptors, but not through 7 receptors, was significantly decreased by treatment with a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 10–30 nM). In addition, PMA (10 nM) selectively promoted a progressive decrease in 7-G423S current induced by repetitive application of ACh pulses (1 mM, 0.1 s, 0.17–0.33 Hz) compared with 7 current. PMA also enhanced the inactivation of 7-G423S mutant receptors induced by a prolonged application of choline (30 µM) without affecting 7 receptor responses. Western blot analysis showed that the treatment with PMA (30 nM) increased the serine phosphorylation level of the 7-G423S mutant receptors but not that of the wild-type receptors. These findings demonstrate that the G423S mutation promotes receptor desensitization by a protein kinase C-dependent mechanism. Thus, we provide the first evidence that a variant in the human CHRNA7 gene alters the function of 7 nicotinic receptors.

Address correspondence to: Dr. Hiroshi Tsuneki, Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: htsuneki{at}pha.u-toyama.ac.jp