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Titolo:
Design and characterization of a highly selective peptide inhibitor of thesmall conductance calcium-activated K+ channel, SkCa2
Autore:
Shakkottai, VG; Regaya, I; Wulff, H; Fajloun, Z; Tomita, H; Fathallah, M; Cahalan, MD; Gargus, JJ; Sabatier, JM; Chandy, KG;
Indirizzi:
Univ Calif Irvine, Sch Med, Dept Physiol & Biophys, Irvine, CA 92697 USA Univ Calif Irvine Irvine CA USA 92697 iol & Biophys, Irvine, CA 92697 USA Fac Med Nord, CNRS, Unite Mixte Rech 6560, F-13014 Marseille, France Fac Med Nord Marseille France F-13014 ch 6560, F-13014 Marseille, France Hop St Marguerite, INSERM, Assistance Publ Hop Marseille, CIC 9502, F-13009 Marseille, France Hop St Marguerite Marseille France F-13009 02, F-13009 Marseille, France
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 46, volume: 276, anno: 2001,
pagine: 43145 - 43151
SICI:
0021-9258(20011116)276:46<43145:DACOAH>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN T-LYMPHOCYTES; POTASSIUM CHANNELS; SCORPION TOXIN; STRUCTURAL CONSERVATION; LEIUROTOXIN-I; APAMIN; CELLS; PHARMACOLOGY; AFFINITY; BRAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Shakkottai, VG Univ Calif Irvine, Sch Med, Dept Physiol & Biophys, Rm 291,Joan Irvine Smith Hall, Irvine, CA 92697 USA Univ Calif Irvine Rm 291,Joan Irvine Smith Hall Irvine CA USA 92697
Citazione:
V.G. Shakkottai et al., "Design and characterization of a highly selective peptide inhibitor of thesmall conductance calcium-activated K+ channel, SkCa2", J BIOL CHEM, 276(46), 2001, pp. 43145-43151

Abstract

Apamin-sensitive small conductance calcium-activated potassium channels (SKCa1-3) mediate the slow afterhyperpolarization in neurons, but the molecular identity of the channel has not been defined because of the lack of specific inhibitors. Here we describe the structure-based design of a selectiveinhibitor of SKCa2. Leiurotoxin I (Lei) and PO5, peptide toxins that sharethe RXCQ motif, potently blocked human SKCa2 and SKCa3 but not SKCa1, whereas maurotoxin, Pi1, Tsk, and PO1 were ineffective. Lei blocked these channels more potently than PO5 because of the presence of Ala(1), Phe(2), and Met(7). By replacing Met(7) in the RXCQ motif of Lei with the shorter, unnatural, positively charged diaminobutanoic acid (Dab), we generated Lei-Dab(7), a selective SKCa2 inhibitor (K-d = 3.8 nM) that interacts with residues in the external vestibule of the channel. SKCa3 was rendered sensitive to Lei-Dab(7) by replacing His(521) with the corresponding SKCa2 residue (Asn(367)). Intracerebroventricular injection of Lei-Dab(7) into mice resulted inno gross central nervous system toxicity at concentrations that specifically blocked SKCa2 homotetramers. Lei-Dab(7) will be a useful tool to investigate the functional role of SKCa2 in mammalian tissues.

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Documento generato il 30/11/20 alle ore 12:23:35