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

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 cyto-plasmic 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 tech-nique. 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, 10–3