Adenosine diphosphate as an intracellular regulator of insulin secretion.
Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated KATP channels that could be opened by diazoxide but not in response to metabolic inhibition. The hamster SUR, containing the analogous mutation, had normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted in the same phenotype, whereas an equivalent mutation in NBF1 showed normal sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP inhibition of KATP++ channels, intracellular MgADP may regulate insulin secretion.
Nichols
C G
CG
Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. cnichols@cellbio.wustl.edu
Shyng
S L
SL
Nestorowicz
A
A
Glaser
B
B
Clement
J P
JP
Gonzalez
G
G
Aguilar-Bryan
L
L
Permutt
M A
MA
Bryan
J
J
D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate / Q000378:metabolism* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003981:Diazoxide / Q000494:pharmacology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D012413:Rubidium; D003981:Diazoxide