A novel ABCC8 (SUR1)-dependent mechanism of metabolism-excitation uncoupling.
ATP/ADP-sensing (sulfonylurea receptor (SUR)/K(IR)6)(4) K(ATP) channels regulate the excitability of our insulin secreting and other vital cells via the differential MgATP/ADP-dependent stimulatory actions of their tissue-specific ATP-binding cassette regulatory subunits (sulfonylurea receptors), which counterbalance the nearly constant inhibitory action of ATP on the K(+) inwardly rectifying pore. Mutations in SUR1 that abolish its stimulation have been found in infants persistently releasing insulin. Activating mutations in SUR1 have been shown to cause neonatal diabetes. Here, analyses of K(IR)6.2-based channels with diabetogenic receptors reveal that MgATP-dependent hyper-stimulation of mutant SUR can compromise the ability of K(ATP) channels to function as metabolic sensors. I demonstrate that the channel hyperactivity rises exponentially with the number of hyperstimulating subunits, so small subpopulations of channels with more than two mutant SUR can dominate hyperpolarizing currents in heterozygous patients. I uncovered an attenuated tolbutamide inhibition of the hyperstimulated mutant, which is normally sensitive to the drug under non-stimulatory conditions. These findings show the key role of SUR in sensing the metabolic index in humans and urge others to (re)test mutant SUR/K(IR)6 channels from probands in physiologic MgATP.
Babenko
Andrey P
AP
Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA. ababenko@pnri.org
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D016764:Cell Polarity / Q000187:drug effects / Q000235:genetics; D002522:Chlorocebus aethiops; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008274:Magnesium / Q000378:metabolism*; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D007004:Hypoglycemic Agents; D007328:Insulin; D008274:Magnesium; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human