Long chain CoA esters as competitive antagonists of PIP2 activation in Kir channels. Export

@article{citeulike:300486, abstract = {Long chain fatty acid esters of Coenzyme A (LC-CoA) are potent activators of ATP-sensitive (KATP) channels and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP2) which activates all known inwardly-rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterised. In this study, we show that in contrast to their stimulatory effect on KATP channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, whilst both its activatory and inhibitory effects critically depend on the presence of the 3'ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP2 and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2, and that PIP2 binding can be competitively antagonized by LC-CoA; suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP2. Furthermore, we demonstrate that in contrast to its stimulatory effect on KATP channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of different Kir channel activity by LC-CoA and phosphoinositides, and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity.}, address = {Physiology Dept., University Jena, Jena 07740.}, author = {Rapedius, Markus and Soom, Malle and Shumilina, Ekaterina and Schulze, Dirk and Sch\"{o}nherr, Roland and Kirsch, Cornelia and Lang, Florian and Tucker, Stephen J J. and Baukrowitz, Thomas}, citeulike-article-id = {300486}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M503503200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15980413}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15980413}, comment = {LC-CoA inhibits Kir channles, but activates Katp channels. What the mechanism?? 3'-ribose phosphate is important in LC-CoA effect PI(3,4)P2 inhibits Kir channels!}, day = {24}, doi = {10.1074/jbc.M503503200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {3-ribose, activation, acyl-coa, coa, inhibition, katp, kir, lc-coa, phosphate, pi34p2}, month = {June}, posted-at = {2005-08-22 18:49:28}, priority = {0}, title = {Long chain CoA esters as competitive antagonists of PIP2 activation in Kir channels.}, url = {http://dx.doi.org/10.1074/jbc.M503503200}, year = {2005} }

TY - JOUR ID - citeulike:300486 L3 - citeulike-article-id:300486 N2 - Long chain fatty acid esters of Coenzyme A (LC-CoA) are potent activators of ATP-sensitive (KATP) channels and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP2) which activates all known inwardly-rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterised. In this study, we show that in contrast to their stimulatory effect on KATP channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, whilst both its activatory and inhibitory effects critically depend on the presence of the 3'ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP2 and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2, and that PIP2 binding can be competitively antagonized by LC-CoA; suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP2. Furthermore, we demonstrate that in contrast to its stimulatory effect on KATP channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of different Kir channel activity by LC-CoA and phosphoinositides, and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity. JF - J Biol Chem SN - 0021-9258 AD - Physiology Dept., University Jena, Jena 07740. TI - Long chain CoA esters as competitive antagonists of PIP2 activation in Kir channels. KW - 3-ribose KW - activation KW - acyl-coa KW - coa KW - inhibition KW - katp KW - kir KW - lc-coa KW - phosphate KW - pi34p2 N1 - LC-CoA inhibits Kir channles, but activates Katp channels. What the mechanism?? 3'-ribose phosphate is important in LC-CoA effect PI(3,4)P2 inhibits Kir channels! AU - Rapedius, Markus AU - Soom, Malle AU - Shumilina, Ekaterina AU - Schulze, Dirk AU - Schönherr, Roland AU - Kirsch, Cornelia AU - Lang, Florian AU - Tucker, Stephen J AU - Baukrowitz, Thomas PY - 2005/06/24/ UR - http://dx.doi.org/10.1074/jbc.M503503200 ER -