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Titolo:
Disparate role of Na+ channel D2-S6 residues in batrachotoxin and local anesthetic action
Autore:
Wang, SY; Barile, M; Wang, GK;
Indirizzi:
Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA Harvard UnivBoston MA USA 02115 d, Dept Anesthesia, Boston, MA 02115 USA Brigham & Womens Hosp, Boston, MA 02115 USA Brigham & Womens Hosp Boston MA USA 02115 mens Hosp, Boston, MA 02115 USA SUNY Albany, Dept Biol, Albany, NY 12222 USA SUNY Albany Albany NY USA 12222 Y Albany, Dept Biol, Albany, NY 12222 USA
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 5, volume: 59, anno: 2001,
pagine: 1100 - 1107
SICI:
0026-895X(200105)59:5<1100:DRONCD>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
MUSCLE SODIUM-CHANNEL; POINT MUTATIONS; MOLECULAR DETERMINANTS; FUNCTIONAL EXPRESSION; MYELINATED NERVE; RESISTANCE KDR; SEGMENT IVS6; CURRENTS; INHIBITION; BLOCK;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Wang, GK Harvard Univ, Sch Med, Dept Anesthesia, 75 Francis St, Boston, MA02115 USA Harvard Univ 75 Francis St Boston MA USA 02115 ston, MA 02115 USA
Citazione:
S.Y. Wang et al., "Disparate role of Na+ channel D2-S6 residues in batrachotoxin and local anesthetic action", MOLEC PHARM, 59(5), 2001, pp. 1100-1107

Abstract

Batrachotoxin (BTX) stabilizes the voltage-gated Na+ channels in their open conformation, whereas local anesthetics (LAs) block Na+ conductance. Site-directed mutagenesis has identified clusters of common residues at D1-S6, D3-S6, and D4-S6 segments within the alpha -subunit Na+ channel that are critical for binding of these two types of ligands. In this report, we address whether segment D2-S6 is similarly involved in both BTX and LA actions. Thirteen amino acid positions from G783 to L795 of the rat skeletal muscle Na+ channel (mu1/Skm1) were individually substituted with a lysine residue. Four mutants (N784K, L785K, V787K, and L788K) expressed sufficient Na+ currents for further studies. Activation and/or inactivation gating was alteredin mutant channels; in particular, mu1-V787K displays enhanced slow inactivation and exhibited use-dependent inhibition of peak Na+ currents during repetitive pulses. Two of these four mutants, mu1-N784K and mu1-L788K, were completely resistant to 5 muM BTX. This BTX-resistant phenotype could be caused by structural perturbations induced by a lysine point mutation in the D2-S6 segment. However, these two BTX-resistant mutants remained quite sensitive to bupivacaine block with affinity for inactivated Na+ channels (K-I)of similar to 10 muM or less, which suggests that mu1-N784 and mu1-L788 residues are not in close proximity to the LA binding site.

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Documento generato il 04/04/20 alle ore 11:53:29