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Pharmacological Fractionation of Tetrodotoxin-sensitive Sodium Currents in Rat Dorsal Root Ganglion Neurons by μ-Conotoxins.
MedLine Citation:
PMID:  23351163     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Adult rat dorsal root ganglion (DRG) neurons normally express transcripts for five isoforms of the α-subunit of voltage-gated sodium channels: NaV1.1, 1.6, 1.7, 1.8, and 1.9. Tetrodotoxin (TTX) readily blocks all but NaV1.8 and 1.9, and pharmacological agents that discriminate among the TTX-sensitive NaV1-isoforms are scarce. Recently, we used the activity profile of a panel of μ-conotoxins in blocking cloned rodent NaV1-isoforms expressed in Xenopus laevis oocytes to conclude that action potentials of A- and C-fibers in rat sciatic nerve were, respectively, mediated primarily by NaV1.6 and NaV1.7. EXPERIMENTAL APPROACH: We used three μ-conotoxins, μ-TIIIA, μ-PIIIA and μ-SmIIIA, applied individually and in combinations, to pharmacologically dissect the TTX-sensitive INa of voltage clamped neurons acutely dissociated from adult rat DRG. We examined only small and large neurons whose respective INa were >50% and >80% TTX-sensitive. KEY RESULTS: For both size neurons, the ability of the toxins to block TTX-sensitive INa was μ-TIIIA < μ-PIIIA < μ-SmIIIA, with the latter blocking ≳ 90%. Comparison of the toxin-susceptibility profiles of the neuronal INa with recently-acquired profiles of rat NaV1-isoforms, co-expressed with various NaVβ-subunits in X. laevis oocytes, provided a consistent picture: NaV1.1, 1.6 and 1.7 could account for all of the TTX-sensitive INa, with NaV1.1 < NaV1.6 < NaV1.7 for small neurons and NaV1.7 ≲ NaV1.1 ≲ NaV1.6 for large neurons. CONCLUSIONS AND IMPLICATIONS: Combinations of μ-conotoxins can be used determine the probable Na(V) 1-isoforms underlying the I(Na) in DRG neurons. Preliminary experiments with sympathetic neurons suggest that this approach is extendable to other neurons.
Authors:
Min-Min Zhang; Michael J Wilson; Joanna Gajewiak; Jean E Rivier; Grzegorz Bulaj; Baldomero M Olivera; Doju Yoshikami
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-28
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Affiliation:
Department of Biology, University of Utah, Salt Lake City, Utah, 84112, U.S.A.
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