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| EFFECT OF ATP-SENSITIVE K+ CHANNEL REGULATORS ON CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CHLORIDE CURRENTS |
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| Author(s): SHEPPARD DN, WELSH MJ |
| Source: JOURNAL OF GENERAL PHYSIOLOGY Volume: 100 Issue: 4 Pages: 573-591 Published: OCT 1992 |
| Times Cited: 279 References: 46 |
| Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that is regulated by cAMP-dependent phosphorylation and by intracellular ATP. Intracellular ATP also regulates a class of K+ channels that have a distinct pharmacology: they are inhibited by sulfonylureas and activated by a novel class of drugs called K+ channel openers. In search of modulators of CFTR Cl- channels, we examined the effect of sulfonylureas and K+ channel openers on CFTR Cl- currents in cells expressing recombinant CFTR. The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 muM, respectively. Inhibition by both agents showed little voltage dependence and developed slowly; > 90% inhibition occurred 3 min after adding 1 mM tolbutamide or 100 muM glibenclamide. The effect of tolbutamide was reversible, while that of glibenclamide was not. In contrast to their activating effect on K+ channels, the K+ channel openers, diazoxide, BRL 38227, and minoxidil sulfate inhibited CFTR Cl- currents. Half-maximal inhibition was observed at approximately 250 muM diazoxide, 50 muM BRL 38227, and 40 muM minoxidil sulfate. The rank order of potency for inhibition of CFTR Cl- currents was: glibenclamide > BRL 38227 is-approximately-equal-to minoxidil sulfate > tolbutamide > diazoxide. Site-directed mutations of CFTR in the first membrane-spanning domain and second nucleotide-binding domain did not affect glibenclamide inhibition of CFTR Cl- currents. However, when part of the R domain was deleted, glibenclamide inhibition showed significant voltage dependence. These agents, especially glibenclamide, which was the most potent, may be of value in identifying CFTR Cl- channels. They or related analogues might also prove to be of value in treating diseases such as diarrhea, which may involve increased activity of the CFTR Cl- channel. |
| Document Type: Article |
| Language: English |
Addresses:
1. UNIV IOWA, COLL MED, HOWARD HUGHES MED INST, DEPT INTERNAL MED, 500 EMRB, IOWA CITY, IA 52242 USA
2. UNIV IOWA, COLL MED, DEPT PHYSIOL & BIOPHYS, IOWA CITY, IA 52242 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 |
| Subject Category: Physiology |
| IDS Number: JR761 |
| ISSN: 0022-1295 |
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