Cytoplasmic accumulation of long-chain coenzyme A esters activates KATP and inhibits Kir2.1 channels.

摘要: Long-chain fatty acids acyl coenzyme A esters (LC-CoA) are obligate intermediates of acid metabolism and have been shown to activate KATP channels but inhibit most other Kir (e.g. Kir2.1) by direct channel binding. The activation elevated levels LC-CoA may be involved in the pathophysiology type 2 diabetes, hypothalamic sensing circulating regulation cardiac channels. However, effectively buffered cytoplasm it is currently not clear whether their free concentration can reach sufficient affect vivo. Here, we report that extracellular oleic complexed with albumin at an unbound 81 ± 1 nm strongly activated inhibited Kir2.1 Chinese hamster ovary (CHO) cells as well endogenous currents human embryonic kidney (HEK293) cells. These effects were only seen presence a high glucose (25 mm), condition known promote accumulation inhibiting mitochondrial uptake via carnitine-palmitoyl-transferase-1 (CPT1). Accordingly, pharmacological inhibition CPT1 etomoxir restored under low conditions. Finally, triacsin C, inhibitor acyl-CoA synthetase, which necessary for formation, abolished on various results establish cytoplasmic LC-CoA, might physiological pathophysiological relevance variety tissues.