Muscle-type nicotinic acetylcholine receptor delta subunit determines sensitivity to noncompetitive inhibitors, while gamma subunit regulates divalent permeability

Abstract

Heterologous expression of nicotinic acetylcholine receptor (nAChR) RNAs in Xenopus oocytes was used to examine the structural basis for pharmacological and physiological differences between muscle-type and neuronal nAChRs. Neuronal nAChRs have a higher permeability to calcium than muscle-type nAChRs and display inward rectification, while muscle-type nAChRs have a linear current–voltage relation. In addition, neuronal nAChRs are more sensitive to inhibition by a class of compounds known as “ganglionic blockers”.It has been shown previously that neuronal-muscle hybrid receptors show increased sensitivity to the use-dependent inhibitor of neuronal nAChRs, BTMPS, based on the presence of a neuronal beta subunit. In this study, we report that omission of gamma subunit RNA has a similar effect. αβδ receptors exhibit prolonged inhibition by BTMPS, show a significant permeability to divalent ions, display inward rectification and are more sensitive to mecamylamine. However, while pharmacological effects are associated with the presence of an additional delta subunit, the physiological changes described seem to be associated with the presence or absence of a gamma subunit. These results suggest that, for nAChRs, as is also the case for non-NMDA ionotropic glutamate receptors, the crucial functional property of limiting calcium permeability can be served by a single subunit.