Document Detail

Mechanism of verapamil action on wild-type and slow-channel mutant human muscle acetylcholine receptor.
MedLine Citation:
PMID:  20533996     Owner:  NLM     Status:  MEDLINE    
Verapamil, a Ca(2+) channel blocker widely used in clinical practice, also affects the properties of frog and mouse muscle acetylcholine receptor (AChR). Here, we examine the mechanism of action of verapamil on human wild-type and slow-channel mutant muscle AChRs harboring in any subunit a valine-to-alanine mutation of 13' residue of the pore-lining M2 transmembrane segment. Verapamil, after a pre-treatment of 0.5-10 s, accelerated the decay of whole-cell or macroscopic outside-out currents within milliseconds of ACh application even at clinically attainable doses. Recordings of unitary events in the cell-attached and outside-out configurations showed that verapamil does not alter single-channel conductance, but reduces channel open probability, by prolonging the dwell time into the closed state for wild-type and all mutant AChR. The duration of channel openings decreased only for the epsilonV265A-AChR, by shortening the longest exponential component of the open-time distribution. These results provide a rationale for the therapeutic use of verapamil in the slow-channel syndrome and emphasize the major role played by epsilon subunit in controlling the functional properties of human muscle AChR, as revealed by the peculiar alterations imparted by mutations in this subunit.
Claudia Moriconi; Maria Amalia Di Castro; Sergio Fucile; Fabrizio Eusebi; Francesca Grassi
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-01
Journal Detail:
Title:  Journal of neurochemistry     Volume:  114     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-26     Completed Date:  2010-10-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1231-40     Citation Subset:  IM    
Dipartimento di Fisiologia e Farmacologia, Università La Sapienza, Roma, Italy.
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MeSH Terms
Alanine / genetics
Amino Acid Substitution / genetics
Calcium Channel Blockers / pharmacology
Cells, Cultured
Ion Channel Gating / drug effects,  genetics
Mutation / genetics*
Neuromuscular Junction / drug effects*,  genetics*,  metabolism
Point Mutation / genetics
Reaction Time / drug effects,  genetics
Receptors, Cholinergic / drug effects*,  genetics*,  metabolism
Synaptic Membranes / drug effects,  genetics,  metabolism
Valine / genetics
Verapamil / pharmacology*
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Receptors, Cholinergic; 52-53-9/Verapamil; 56-41-7/Alanine; 7004-03-7/Valine

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