ATP-sensitive K+ channels in insulinoma cells are activated by nonesterified fatty acids.
Both 86Rb+ efflux experiments and electrophysiological studies have shown that arachidonic acid and other nonesterified fatty acids activate ATP-sensitive K+ channels in insulinoma cells (HIT-T15). Activation was observed with arachidonic, oleic, linoleic, and docosahexaenoic acid but not with myristic, stearic, and elaidic acids. Fatty acid activation of ATP-sensitive K+ channels was blocked by antidiabetic sulfonylureas such as glibenclamide. The activating effect of arachidonic acid was unaltered by indomethacin and by nordihydroguaiaretic acid, indicating that it is not due to metabolites of arachidonic acid via cyclooxygenase or lipoxygenase pathways. Moreover, the nonmetabolizable analogue of arachidonic acid, eicosatetraynoic acid, was an equally potent activator. Activation of ATP-sensitive K+ channels by fatty acids was potentiated by diacylglycerol and was inhibited by calphostin C, an inhibitor of protein kinase C. These findings indicate that fatty acid activation of ATP-sensitive K+ channels is most likely due to the participation of arachidonic acid (and other fatty acid)-activated protein kinase C isoenzymes. Activation of ATP-sensitive K+ channels by nonesterified fatty acids is not involved in the control of insulin secretion since arachidonic acid stimulates insulin secretion from insulinoma cells instead of inhibiting it.
Müller
M
M
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
Szewczyk
A
A
De Weille
J R
JR
Lazdunski
M
M
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D007340:Insulinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009840:Oligomycins / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D014407:Tumor Cells, Cultured
D005230:Fatty Acids, Nonesterified; D009840:Oligomycins; D015221:Potassium Channels; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D011493:Protein Kinase C