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A Single Point Mutation Confers Properties of the Muscle-Type Nicotinic Acetylcholine Receptor to Homomeric 7 Receptors

Department of Pharmacology and Therapeutics, J. Hillis Miller Health Science Center, University of Florida, Gainesville, Florida (A.N.P., T.P., E.M.M., R.L.P.); and Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartmento di Fisiologia Umana e Farmacologia, Universita' di Roma "La Sapienza", Roma, Italy (F.G.)

Although the muscle-type and homomeric 7-type nicotinic acetylcholine receptors (nAChRs) share many structural features and bind -bungarotoxin with high affinity, several important functional and pharmacological properties distinguish these two major nAChR subtypes. We have shown previously that amino acid sequence in the second transmembrane (TM) domain of the subunit is critical for pharmacological distinction between muscle type and heteromeric neuronal (e.g., ganglionic) nAChRs. We tested the hypothesis that homologous substitution of amino acid sequence from the muscle 1 subunit into the 7 subunit would confer specific properties of muscle-type receptors to mutant 7 nAChRs. In this study, we show that a single amino acid substitution at the 7 TM2 6' position makes both biophysical and pharmacological properties of the mutant receptors resemble those of wild-type muscle nAChR. This mutation produces significant changes in acetylcholine potency and response kinetics, eliminating the characteristic fast desensitization of 7 and dramatically reducing divalent ion permeability relative to wild-type 7. The TM2 T6'F mutation also produces a profound increase in activation by succinylcholine compared with either wild-type 7 or neuronal -subunit-containing receptors and the loss of potentiation by 5-hydroxyindole. Thus, the 7 TM2 T6'F mutant displays several features that are similar to the muscle nAChR, some of which are not typically thought to be regulated by the pore-lining domain of the receptor.

Address correspondence to: Roger L. Papke, Department of Pharmacology and Therapeutics, Box 100267, JHMHSC, University of Florida, Gainesville, FL 32610-0267. E-mail: rpapke{at}college.med.ufl.edu

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