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The essential role of the Walker A motifs of SUR1 in K‐ATP channel activation by Mg‐ADP and diazoxide
Author(s) -
Gribble Fiona M.,
Tucker Stephen J.,
Ashcroft Frances M.
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.6.1145
Subject(s) - diazoxide , biology , sulfonylurea receptor , adenosine triphosphate , biochemistry , potassium channel , genetics , biophysics , endocrinology , gene , protein subunit , insulin
The ATP‐sensitive K‐channel (K‐ATP channel) plays a key role in insulin secretion from pancreatic β‐cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP and Mg‐ADP, which inhibit and potentiate channel activity, respectively. The β‐cell K‐ATP channel consists of a pore‐forming subunit, Kir6.2, and a regulatory subunit, SUR1. We have mutated (independently or together) two lysine residues in the Walker A (W A ) motifs of the first (K719A) and second (K1384M) nucleotide‐binding domains (NBDs) of SUR1. These mutations are expected to inhibit nucleotide hydrolysis. Our results indicate that the W A lysine of NBD1 (but not NBD2) is essential for activation of K‐ATP currents by diazoxide. The potentiatory effects of Mg‐ADP required the presence of the W A lysines in both NBDs. Mutant currents were slightly more sensitive to ATP than wild‐type currents. Metabolic inhibition led to activation of wild‐type and K1384M currents, but not K719A or K719A/K1384M currents, suggesting that there may be a factor in addition to ATP and ADP which regulates K‐ATP channel activity.