Saturated and cis/trans unsaturated acyl CoA esters differentially regulate wild-type and polymorphic beta-cell ATP-sensitive K+ channels.
Metabolic regulation of pancreatic beta-cell ATP-sensitive K+ channel (K(ATP) channel) function plays a key role in the process of glucose-stimulated insulin secretion (GSIS). Modulation of K(ATP) channel activity by long-chain acyl CoAs represents an important endogenous regulatory mechanism. Elevated acyl CoA levels have been reported in obese and type 2 diabetic individuals and may contribute to reduced beta-cell excitability and impaired GSIS. Recent studies suggest that the composition of dietary fat may influence the effects of high-fat feeding on impaired GSIS. Therefore, we examined the effects of side-chain length and the degree of saturation of various acyl CoAs on K(ATP) channel activity. Macroscopic currents from either wild-type or polymorphic (Kir6.2[E23K/I337V]) recombinant beta-cell K(ATP) channels were measured in inside-out patches by exposing the inner surface of the membrane to acyl CoAs at physiological nanomolar concentrations. Acyl CoAs increased both wild-type and polymorphic K(ATP) channel activity with the following rank order of efficacy: C18:0, C18:1trans approximately C18:1cis, C20:4 = C16:0, C16:1, and C18:2. A significant correlation exists between activation and acyl CoA hydrophobicity, suggesting that both side-chain length and degree of saturation are critical determinants of K(ATP) channel activation. Our observations reveal a plausible mechanism behind the disparate effects of acyl CoA saturation on K(ATP) channel activation and suggest that dietary fat composition may determine the severity of impaired GSIS via differential activation of beta-cell K(ATP) channels.
Riedel
Michael J
MJ
Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building, Edmonton, Alberta T6G 2H7, Canada.
Light
Peter E
PE
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D011110:Polymorphism, Genetic; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D013329:Structure-Activity Relationship; D000099161:Kcnj11 Channel
D000214:Acyl Coenzyme A; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel