Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells.
The role of adenylate kinase (AK) as a determinant of K-ATP channel activity in human pancreatic beta-cells was investigated. We have identified that two cytosolic isoforms of AK, AK1 and AK5 are expressed in human islets and INS-1 cells. Elevated concentrations of glucose inhibit AK1 expression and AK1 immunoprecipitates with the Kir6.2 subunit of K-ATP. AK activation by ATP+AMP stimulates K-ATP channel activity and this stimulation is abolished by AK inhibitors. We propose that glucose stimulation of beta-cells inhibits AK through glycolysis and also through the elevation of diadenosine polyphosphate levels. Glucose-dependent inhibition of AK increases the ATP/ADP ratio in the microenvironment of the K-ATP channel promoting channel closure and insulin secretion. The down-regulation of AK1 expression by hyperglycemia may contribute to the defective coupling of glucose metabolism to K-ATP channel activity in type 2 diabetes.
Stanojevic
Violeta
V
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Habener
Joel F
JF
Holz
George G
GG
Leech
Colin A
CA
D000263:Adenylate Kinase / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats
D007328:Insulin; D007527:Isoenzymes; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000263:Adenylate Kinase; C110939:adenylate kinase 1; C118782:adenylate kinase 5; D000262:Adenylyl Cyclases; D005947:Glucose