title: Cytoplasmic accumulation of long-chain coenzyme A esters activates KATP and inhibits Kir2.1 channels.
abstract: Long-chain fatty acids acyl coenzyme A esters (LC-CoA) are obligate intermediates of fatty acid metabolism and have been shown to activate K(ATP) channels but to inhibit most other Kir channels (e.g. Kir2.1) by direct channel binding. The activation of K(ATP) channels by elevated levels of LC-CoA may be involved in the pathophysiology of type 2 diabetes, the hypothalamic sensing of circulating fatty acids and the regulation of cardiac K(ATP) channels. However, LC-CoA are effectively buffered in the cytoplasm and it is currently not clear whether their free concentration can reach levels sufficient to affect Kir channels in vivo. Here, we report that extracellular oleic acid complexed with albumin at an unbound concentration of 81 +/- 1 nm strongly activated K(ATP) channels and inhibited Kir2.1 channels in Chinese hamster ovary (CHO) cells as well as endogenous Kir currents in human embryonic kidney (HEK293) cells. These effects were only seen in the presence of a high concentration of glucose (25 mm), a condition known to promote the accumulation of LC-CoA by inhibiting their mitochondrial uptake via carnitine-palmitoyl-transferase-1 (CPT1). Accordingly, pharmacological inhibition of CPT1 by etomoxir restored the effects of oleic acid under low glucose conditions. Finally, triacsin C, an inhibitor of the acyl-CoA synthetase, which is necessary for LC-CoA formation, abolished the effects of extracellular oleic acid on the various Kir channels. These results establish the direct regulation of Kir channels by the cytoplasmic accumulation of LC-CoA, which might be of physiological and pathophysiological relevance in a variety of tissues.
authors.affiliation: Institute of Physiology II, Friedrich Schiller University, Jena, Teichgraben 8, 07743 Jena, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Shumilina
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
authors.forename: Ganna
authors.initials: G
authors.lastname: Korniychuk
authors.forename: Markus
authors.initials: M
authors.lastname: Rapedius
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Thomas
authors.initials: T
authors.lastname: Baukrowitz
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000418:Albumins / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003065:Coenzyme A / Q000378:metabolism*; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism*; D004952:Esters; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019301:Oleic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology
chemical_list: D000214:Acyl Coenzyme A; D000418:Albumins; D004952:Esters; C489457:KCNJ2 protein, human; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C117780:mitochondrial K(ATP) channel; C017585:oleoyl-coenzyme A; D019301:Oleic Acid; D005947:Glucose; D003065:Coenzyme A