Abstract

Binding of a neurotransmitter to its membrane receptor opens an integral ion conducting pore. However, prolonged exposure to the neurotransmitter drives the receptor to a refractory state termed desensitization, which plays an important role in shaping synaptic transmission. Despite intensive research in the past, the structural mechanism of desensitization is still elusive. Using mutagenesis and voltage clamp in an oocyte expression system, we provide several lines of evidence supporting a novel hypothesis that uncoupling between binding and gating machinery is the underlying mechanism for α7 nicotinic receptor (nAChR) desensitization. First, the decrease in gate tightness was highly correlated to the reduced desensitization. Second, nonfunctional mutants in three important coupling loops (loop 2, loop 7, and the M2-M3 linker) could be rescued by a gating mutant. Furthermore, the decrease in coupling strength in these rescued coupling loop mutants reversed the gating effect on desensitization. Finally, coupling between M1 and hinge region of the M2-M3 linker also influenced the receptor desensitization. Thus, the uncoupling between N-terminal domain and transmembrane domain, governed by the balance of coupling strength and gate tightness, underlies the mechanism of desensitization for the α7 nAChR.

Highlights

  • The Cys-loop receptor family of ligand-gated ion channels are allosteric proteins [1,2,3,4]

  • Another study using serotonin receptor type 3 (5HT3R) chimeric with ␣7 nAChR fragments suggests that the interface between N-terminal domain and transmembrane domain, especially pre-M1 and the M2-M3 linker, is an important determinant for desensitization [22]

  • We proposed a novel hypothesis that uncoupling of N-terminal domain and transmembrane domain is a major mechanism for receptor desensitization, and this uncoupling is mainly determined by the balance of coupling strength and gate tight

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Summary

Introduction

The Cys-loop receptor family of ligand-gated ion channels are allosteric proteins [1,2,3,4]. We proposed a novel hypothesis that uncoupling of N-terminal domain and transmembrane domain is a major mechanism for receptor desensitization, and this uncoupling is mainly determined by the balance of coupling strength (between loop 2/loop 7/M1 and M2-M3 linker) and gate tight-

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