Insulin-like growth factor-I inhibits rat arterial K(ATP) channels through pI 3-kinase.
Since, in addition to its growth-promoting actions, insulin-like growth factor-I (IGF-I) has rapid vasoactive actions, we investigated the effects of IGF-I on whole-cell ATP-sensitive K(+) (K(ATP)) currents of rat mesenteric arterial smooth muscle cells. IGF-I (10 or 30 nM) reduced K(ATP) currents activated by pinacidil or a membrane permeant cAMP analogue. Inhibition of phospholipase C, protein kinase C, protein kinase A, mitogen-activated protein kinase or mammalian target of rapamycin (mTOR) did not prevent the action of IGF-I. However, inhibition of K(ATP) currents by IGF-I was abolished by the tyrosine kinase inhibitor genistein or the phosphoinositide 3-kinase inhibitors, LY 294002 and wortmannin. Intracellular application of either phosphatidylinositol 4,5-bisphosphate (PIP(2)) or phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) increased the K(ATP) current activated by pinacidil and abolished the inhibitory effect of IGF-I. Thus, we show regulation of arterial K(ATP) channels by polyphosphoinositides and report for the first time that IGF-I inhibits these channels via a phosphoinositide 3-kinase-dependent pathway.
Hayabuchi
Y
Y
Department of Cell Physiology and Pharmacology, Ion Channel Group, University of Leicester, P.O. Box 138, Leicester LE1 9HN, UK.
Willars
G B
GB
Standen
N B
NB
Davies
N W
NW
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D054801:Phosphoinositide Phospholipase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020110:Pinacidil / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D017868:Cyclic AMP-Dependent Protein Kinases; D019833:Genistein; D007334:Insulin-Like Growth Factor I; D054086:KATP Channels; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D054801:Phosphoinositide Phospholipase C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020110:Pinacidil; D011493:Protein Kinase C; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C060974:phosphatidylinositol 3,4,5-triphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat