Document Detail


Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins.
MedLine Citation:
PMID:  23146020     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Voltage-gated sodium channels (VGSCs) are assembled from two classes of subunits, a pore-bearing α-subunit (NaV 1) and one or two accessory β-subunits (NaV βs). Neurons in mammals can express one or more of seven isoforms of NaV 1 and one or more of four isoforms of NaV β. The peptide μ-conotoxins, like the guanidinium alkaloids tetrodotoxin (TTX) and saxitoxin (STX), inhibit VGSCs by blocking the pore in NaV 1. Hitherto, the effects of NaV β-subunit co-expression on the activity of these toxins have not been comprehensively assessed.
EXPERIMENTAL APPROACH: Four μ-conotoxins (μ-TIIIA, μ-PIIIA, μ-SmIIIA and μ-KIIIA), TTX and STX were tested against NaV 1.1, 1.2, 1.6 or 1.7, each co-expressed in Xenopus laevis oocytes with one of NaV β1, β2, β3 or β4 and, for NaV 1.7, binary combinations of thereof.
KEY RESULTS: Co-expression of NaV β-subunits modifies the block by μ-conotoxins: in general, NaV β1 or β3 co-expression tended to increase kon (in the most extreme instance by ninefold), whereas NaV β2 or β4 co-expression decreased kon (in the most extreme instance by 240-fold). In contrast, the block by TTX and STX was only minimally, if at all, affected by NaV β-subunit co-expression. Tests of NaV β1 : β2 chimeras co-expressed with NaV 1.7 suggest that the extracellular portion of the NaV β subunit is largely responsible for altering μ-conotoxin kinetics.
CONCLUSIONS AND IMPLICATIONS: These results are the first indication that NaV β subunit co-expression can markedly influence μ-conotoxin binding and, by extension, the outer vestibule of the pore of VGSCs. μ-Conotoxins could, in principle, be used to pharmacologically probe the NaV β subunit composition of endogenously expressed VGSCs.
Authors:
Min-Min Zhang; Michael J Wilson; Layla Azam; Joanna Gajewiak; Jean E Rivier; Grzegorz Bulaj; Baldomero M Olivera; Doju Yoshikami
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1597-610     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Animals
Conotoxins / pharmacology*
Female
Kinetics
Oocytes / metabolism
Protein Isoforms / metabolism
Rats
Sodium Channel Blockers / pharmacology*
Voltage-Gated Sodium Channel beta Subunits / metabolism
Voltage-Gated Sodium Channels / metabolism*
Xenopus laevis
Grant Support
ID/Acronym/Agency:
GM 48677/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Conotoxins; 0/Protein Isoforms; 0/Sodium Channel Blockers; 0/Voltage-Gated Sodium Channel beta Subunits; 0/Voltage-Gated Sodium Channels
Comments/Corrections

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