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Titolo:
Mechanism of terfenadine block of ATP-sensitive K+ channels
Autore:
Zunkler, BJ; Kuhne, S; Rustenbeck, I; Ott, T;
Indirizzi:
Fed Inst Drugs & Med Devices, D-13353 Berlin, Germany Fed Inst Drugs & MedDevices Berlin Germany D-13353 3353 Berlin, Germany Hannover Med Sch, Inst Clin Biochem, D-30623 Hannover, Germany Hannover Med Sch Hannover Germany D-30623 hem, D-30623 Hannover, Germany
Titolo Testata:
BRITISH JOURNAL OF PHARMACOLOGY
fascicolo: 7, volume: 130, anno: 2000,
pagine: 1571 - 1574
SICI:
0007-1188(200008)130:7<1571:MOTBOA>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
2ND-GENERATION ANTIHISTAMINES; RECEPTOR; KIR6.2; HERG; ASTEMIZOLE;
Keywords:
terfenadine; K-ATP channels; pH-dependence; pore-forming Kir6.2 subunit;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
14
Recensione:
Indirizzi per estratti:
Indirizzo: Zunkler, BJ Fed Inst Drugs & Med Devices, Seestr 10, D-13353 Berlin, Germany Fed Inst Drugs & Med Devices Seestr 10 Berlin Germany D-13353
Citazione:
B.J. Zunkler et al., "Mechanism of terfenadine block of ATP-sensitive K+ channels", BR J PHARM, 130(7), 2000, pp. 1571-1574

Abstract

1 The ATP-sensitive K+ (K-ATP) channel is a complex of a pore-forming inwardly rectifying K+ channel (Kir6.2) and a sulphonylurea receptor (SUR). Theaim of the present study was to gain further insight into the mechanism ofblock of K-ATP channels by terfenadine.2 Channel activity was recorded both from native K-ATP channels from the clonal insulinoma cell line RINm5F and from a C-terminal truncated form of Kir6.2 (Kir6.2 Delta 26), which - in contrast to Kir6.2 - expresses independently of SUR. Kir6.2 Delta 26 channels were expressed in COS-7 cells, and enhanced green fluorescent protein (EGFP) cDNA was used as a reporter gene. EGFP fluorescence was visualized by a laser scanning confocal microscope.3 Terfenadine applied to the cytoplasmic side of inside-out membrane patches concentration-dependently blocked both native K-ATP channel and Kir6.2 Delta 26 channel activity, and the following values were calculated for IC50(the terfenadine concentration causing half-maximal inhibition) and n (theHill coefficient): 1.2 mu M and 0.7 for native K-ATP channels, 3.0 mu M and 1.0 for Kir6.2 Delta 26 channels.4 Terfenadine had no effect on slope conductance of either native K-ATP channels or Kir6.2 Delta 26 channels. Intraburst kinetics of Kir6.2 Delta 26 channels were not markedly affected by terfenadine and, therefore, terfenadine acts as a slow channel blocker on Kir6.2 Delta 26 channels. Terfenadine-induced block of Kir6.2 Delta 26 channels demonstrated no marked voltage dependence, and lowering the intracellular pH to 6.5 potentiated the inhibition of Kir6.2 Delta 26 channels by terfenadine.5 These observations indicate that terfenadine blocks pancreatic B-cell K-ATP channels via binding to the cytoplasmic side of the pore-forming subunit. The presence of the pancreatic SUR1 has a small, but significant enhancing effect on the potency of terfenadine.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/18 alle ore 08:27:45