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MOLECULAR AND GENOMIC |
1 Institute of Physiology I, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany
2 Institute of Physiology II, University of Freiburg, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany
3 Institute of Physiology II, Friedrich Schiller University Jena, Teichgraben 8, 07743 Jena, Germany
Long-chain fatty acids acyl coenzyme A esters (LC-CoA) are obligate intermediates of fatty acid metabolism and have been shown to activate KATP channels but to inhibit most other Kir channels (e.g. Kir2.1) by direct channel binding. The activation of KATP 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 KATP 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 KATP 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.
(Received 6 April 2006;
accepted after revision 15 June 2006;
first published online 15 June 2006)
Corresponding author T. Baukrowitz: Institute of Physiology II, Friedrich Schiller University, Jena, Teichgraben 8, 07743 Jena, Germany. Email: thomas.baukrowitz{at}mti.uni-jena.de
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