Involvement of 3Na+/2K+ ATP-ase and Pi-3 kinase in the response of skeletal muscle ATP-sensitive K+ channels to insulin.
The modulation of ATP-sensitive K+ channel (K(ATP)) by insulin plays a role in neuromuscular disorders associated to altered K+ homeostasis. However, the mechanisms by which insulin modulates K(ATP) channels are not known. Here, the insulin-dependent 3Na+/2K+ ATP-ase and Pi-3 kinase pathways were explored by using patch-clamp techniques. High and low affinity inhibition of K(ATP) channels by ouabain was observed in the insulin-stimulated and resting fibers, respectively. The 9A5 antibody directed against the alpha1-subunit of the pump inhibited the K(ATP) channel in the resting fibers but fails to inhibit it in the insulin-stimulated fibers. In contrast, the RT2NKATPabr, an alpha2-subunit specific antibody, inhibited the K(ATP) channels in the insulin-stimulated fibers failing to inhibit it in the resting fibers. The insulin-dependent stimulation of K(ATP) channel was prevented by Pi-3 kinase inhibitors Wortmannin and LY294002. In conclusion, insulin stimulating the 3Na+/2K+ ATP-ase activates K(ATP) channels through a membrane-delimited interaction thus controlling the K+ homeostasis. The Pi-3 kinase is the intracellular insulin signal linking the glucose homeostasis to the K(ATP) channel.
Tricarico
Domenico
D
Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, via Orabona no 4, University of Bari, I-70126, Bari, Italy. dtricarico@farmbiol.uniba.it
Montanari
Loredana
L
Conte Camerino
Diana
D
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000276:immunology / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D002867:Chromones; D004791:Enzyme Inhibitors; D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D009025:Morpholines; D010042:Ouabain; D019869:Phosphatidylinositol 3-Kinases; D015221:Potassium Channels; D000254:Sodium-Potassium-Exchanging ATPase; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one