RT Journal Article
SR Electronic
T1 A Single Point Mutation Confers Properties of the Muscle-Type Nicotinic Acetylcholine Receptor to Homomeric α7 Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 169
OP 177
DO 10.1124/mol.66.1.169
VO 66
IS 1
A1 Andon N. Placzek
A1 Francesca Grassi
A1 Thaddeus Papke
A1 Edwin M. Meyer
A1 Roger L. Papke
YR 2004
UL http://molpharm.aspetjournals.org/content/66/1/169.abstract
AB Although the muscle-type and homomeric α7-type nicotinic acetylcholine receptors (nAChRs) share many structural features and bind α-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 β 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 β1 subunit into the α7 subunit would confer specific properties of muscle-type receptors to mutant α7 nAChRs. In this study, we show that a single amino acid substitution at the α7 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 α7 and dramatically reducing divalent ion permeability relative to wild-type α7. The TM2 T6′F mutation also produces a profound increase in activation by succinylcholine compared with either wild-type α7 or neuronal β-subunit-containing receptors and the loss of potentiation by 5-hydroxyindole. Thus, the α7 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.