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XB-ART-46218
Br J Pharmacol 2013 Apr 01;1687:1597-610. doi: 10.1111/bph.12051.
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Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins.

Zhang MM , Wilson MJ , Azam L , Gajewiak J , Rivier JE , Bulaj G , Olivera BM , Yoshikami D .


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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. 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. 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. 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.

???displayArticle.pubmedLink??? 23146020
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References [+] :
Alexander, Guide to Receptors and Channels (GRAC), 5th edition. 2011, Pubmed