Block of muscle nicotinic receptors by choline suggests that the activation and desensitization gates act as distinct molecular entities

The Journal of General Physiology
Yamini Purohit, Claudio Grosman

Abstract

Ion channel block in muscle acetylcholine nicotinic receptors (AChRs) is an extensively reported phenomenon. Yet, the mechanisms underlying the interruption of ion flow or the interaction of the blocker with the channel's gates remain incompletely characterized. In this paper, we studied fast channel block by choline, a quaternary-ammonium cation that is also an endogenous weak agonist of this receptor, and a valuable tool in structure-function studies. Analysis of the single-channel current amplitude as a function of both choline concentration and voltage revealed that extracellular choline binds to the open-channel pore with millimolar apparent affinity (K(B) congruent with 12 mM in the presence of approximately 155 mM monovalent and 3.5 mM divalent, inorganic cations), and that it permeates the channel faster than acetylcholine. This, together with its relatively small size ( approximately 5.5 A along its longest axis), suggests that the pore-blocking choline binding site is the selectivity filter itself, and that current blockages simply reflect the longer-lived sojourns of choline at this site. Kinetic analysis of single-channel traces indicated that increasing occupancy of the pore-blocking site by choline (as judged from...Continue Reading

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Methods Mentioned

BETA
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Software Mentioned

SPSS
QuB
SigmaPlot
VMD
OA

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