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The tolbutamide site of SUR1 and a mechanism for its functional coupling to K ATP channel closure
Author(s) -
Babenko Andrey P,
Gonzalez Gabriela,
Bryan Joseph
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)01215-6
Subject(s) - tolbutamide , sulfonylurea receptor , kir6.2 , biophysics , chemistry , protein subunit , nucleotide , intracellular , potassium channel , diazoxide , glibenclamide , biochemistry , biology , insulin , endocrinology , diabetes mellitus , gene
Micromolar concentrations of tolbutamide will inhibit (SUR1/K IR 6.2) 4 channels in pancreatic β‐cells, but not (SUR2A/K IR 6.2) 4 channels in cardiomyocytes. Inhibition does not require Mg 2+ or nucleotides and is enhanced by intracellular nucleotides. Using chimeras between SUR1 and SUR2A, we show that transmembrane domains 12–17 (TMD12‐17) are required for high‐affinity tolbutamide inhibition of K ATP channels. Deletions demonstrate involvement of the cytoplasmic N‐terminus of K IR 6.2 in coupling sulfonylurea‐binding with SUR1 to the stabilization of an interburst closed configuration of the channel. The increased efficacy of tolbutamide by nucleotides results from an impairment of their stimulatory action on SUR1 which unmasks their inhibitory effects. The mechanism of inhibition of β‐cell K ATP channels by sulfonylureas during treatment of non‐insulin‐dependent diabetes mellitus thus involves two components, drug‐binding and conformational changes within SUR1 which are coupled to the pore subunit through its N‐terminus and the disruption of nucleotide‐dependent stimulatory effects of the regulatory subunit on the pore. These findings uncover a molecular basis for an inhibitory influence of SUR1, an ATP‐binding cassette (ABC) protein, on K IR 6.2, a ion channel subunit.