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• W2093537983 abstract "Insulin secretion from pancreatic beta cells is coupled to cell metabolism through closure of ATP-sensitive potassium (KATP) channels, which comprise Kir6.2 and sulfonylurea receptor (SUR1) subunits. Although metabolic regulation of KATP channel activity is believed to be mediated principally by the adenine nucleotides, other metabolic intermediates, including long chain acyl-CoA esters, may also be involved. We recorded macroscopic and single-channel currents from Xenopusoocytes expressing either Kir6.2/SUR1 or Kir6.2ΔC36 (which forms channels in the absence of SUR1). Oleoyl-CoA (1 μm) activated both wild-type Kir6.2/SUR1 and Kir6.2ΔC36 macroscopic currents, ∼2-fold, by increasing the number and open probability of Kir6.2/SUR1 and Kir6.2ΔC36 channels. It was ineffective on the related Kir subunit Kir1.1a. Oleoyl-CoA also impaired channel inhibition by ATP, increasing the Ki values for both Kir6.2/SUR1 and Kir6.2ΔC36 currents by ∼3-fold. Our results indicate that activation of KATP channels by oleoyl-CoA results from an interaction with the Kir6.2 subunit, unlike the stimulatory effects of MgADP and diazoxide which are mediated through SUR1. The increased activity and reduced ATP sensitivity of KATP channels by oleoyl-CoA might contribute to the impaired insulin secretion observed in non-insulin-dependent diabetes mellitus. Insulin secretion from pancreatic beta cells is coupled to cell metabolism through closure of ATP-sensitive potassium (KATP) channels, which comprise Kir6.2 and sulfonylurea receptor (SUR1) subunits. Although metabolic regulation of KATP channel activity is believed to be mediated principally by the adenine nucleotides, other metabolic intermediates, including long chain acyl-CoA esters, may also be involved. We recorded macroscopic and single-channel currents from Xenopusoocytes expressing either Kir6.2/SUR1 or Kir6.2ΔC36 (which forms channels in the absence of SUR1). Oleoyl-CoA (1 μm) activated both wild-type Kir6.2/SUR1 and Kir6.2ΔC36 macroscopic currents, ∼2-fold, by increasing the number and open probability of Kir6.2/SUR1 and Kir6.2ΔC36 channels. It was ineffective on the related Kir subunit Kir1.1a. Oleoyl-CoA also impaired channel inhibition by ATP, increasing the Ki values for both Kir6.2/SUR1 and Kir6.2ΔC36 currents by ∼3-fold. Our results indicate that activation of KATP channels by oleoyl-CoA results from an interaction with the Kir6.2 subunit, unlike the stimulatory effects of MgADP and diazoxide which are mediated through SUR1. The increased activity and reduced ATP sensitivity of KATP channels by oleoyl-CoA might contribute to the impaired insulin secretion observed in non-insulin-dependent diabetes mellitus. ATP-sensitive potassium channel sulfonylurea receptor long chain bovine serum albumin phosphatidylinositol bisphosphate. Potassium channels that are inhibited by ATP (KATPchannels)1 are found in many tissues, where they serve to couple the metabolic state of the cell to its electrical activity (1Ashcroft F.M. Annu. Rev. Neurosci. 1988; 11: 97-118Crossref PubMed Scopus (767) Google Scholar). In the pancreatic beta cell, for example, they provide the link between changes in blood glucose concentration and insulin secretion. The KATP channel sets the beta cell resting membrane potential, and its closure in response to glucose metabolism elicits membrane depolarization, activation of voltage-gated Ca2+ channels, and a rise in Ca2+ influx that stimulates insulin release (2Ashcroft F.M. Rorsman P. Prog. Biophys. Mol. Biol. 1989; 54: 87-143Crossref PubMed Scopus (945) Google Scholar). In cardiac muscle, and in brain neurons, KATP channels may be involved in the response to ischemia, whereas in smooth muscle they are important for the regulation of vascular tone (3Nichols C.G. Lederer W.J. Am. J. Physiol. 1991; 261: H1675-H1686PubMed Google Scholar, 4Quayle J.M. Nelson M.T. Standen N.B. Physiol. Rev. 1997; 77: 1165-1232Crossref PubMed Scopus (708) Google Scholar).KATP channels are formed by the physical association of four inwardly rectifying K+ channel (Kir6.2) subunits with four sulfonylurea receptor (SUR) subunits (5Clement J.P., IV Kunjilwar K. Gonzalez G. Schwanstecher M. Panten U. Aguilar-Bryan L. Bryan J. Neuron. 1997; 18: 827-838Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar, 6Inagaki N. Gonoi T. Seino S. FEBS Lett. 1997; 409: 232-236Crossref PubMed Scopus (244) Google Scholar, 7Shyng S.-L. Nichols C.G. J. Gen. Physiol. 1997; 110: 655-664Crossref PubMed Scopus (418) Google Scholar). Kir6.2 serves as an ATP-sensitive pore that is common to many types of KATPchannels. SUR is a regulatory subunit that modulates the channel gating properties, enhances the apparent ATP-sensitivity, and acts as the target for sulfonylurea drugs, K-channel openers and intracellular Mg-nucleotides, which modulate KATP channel activity (8Nichols C.G. Shyng S.-L. Nestorowicz A,. Glaser B. Clement J.P., IV Gonzalez G. Aguilar-Bryan L. Permutt M.A. Bryan J. Science. 1996; 272: 1785-1787Crossref PubMed Scopus (467) Google Scholar, 9Gribble F.M. Tucker S.J. Ashcroft F.M. EMBO J. 1997; 16: 1145-1152Crossref PubMed Scopus (310) Google Scholar, 10Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 643-654Crossref PubMed Scopus (246) Google Scholar, 11Trapp S. Tucker S.J. Ashcroft F.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8872-8877Crossref PubMed Scopus (54) Google Scholar, 12Tucker S.J. Gribble F.M. Zhao C. Trapp S. Ashcroft F.M. Nature. 1997; 378: 179-183Crossref Scopus (675) Google Scholar). It is currently believed that Kir6.2/SUR1 forms the beta cell KATP channel, Kir6.2/SUR2A forms the cardiac KATP channel, and Kir6.2/SUR2B forms the smooth muscle KATP channel (13Inagaki N. Gonoi T. Clement J.P. Namba N. Inazawa J. Gonzalez G. Aguilar-Bryan L. Seino S. Bryan J. Science. 1995; 270: 1166-1169Crossref PubMed Scopus (1607) Google Scholar, 14Inagaki N. Gonoi T. Clement J.P., IV Wang C.Z. Aguilar-Bryan L. Bryan J. Seino S. Neuron. 1996; 16: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar, 15Sakura H. Ämmälä C. Smith P.A. Gribble F.M. Ashcroft F.M. FEBS Lett. 1995; 377: 338-344Crossref PubMed Scopus (402) Google Scholar, 16Chutkow W.A. Simon M.C. Le Beau M.M. Burant C.F. Diabetes. 1996; 45: 1439-1445Crossref PubMed Scopus (225) Google Scholar, 17Isomoto S. Kondo C. Yamada M. Matsumoto S. Higashiguchi O. Horio Y. Matsuzawa Y. Kurachi Y. J. Biol. Chem. 1996; 271: 24321-24325Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar).It has recently been shown that long chain (LC) acyl-CoA esters are able to activate native KATP channels in inside-out membrane patches excised from pancreatic beta cells (18Larsson O. Deeney J.T. Bränström R. Berggren P-O. Corkey B.E. J. Biol. Chem. 1996; 271: 10623-10626Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). The intracellular concentrations of LC acyl-CoA esters are predicted to vary with the metabolic state of the cell. Because long-term exposure to nonesterified fatty acids increases cellular levels of LC acyl-CoA esters in the beta cell (18Larsson O. Deeney J.T. Bränström R. Berggren P-O. Corkey B.E. J. Biol. Chem. 1996; 271: 10623-10626Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 20Prentki M. Vischer S. Glennon M.C. Regazzi R. Deeney J.T. Corkey B.E. J. Biol. Chem. 1992; 267: 5802-5810Abstract Full Text PDF PubMed Google Scholar), this finding may have implications for the regulation of insulin secretion under conditions in which nonesterified fatty acids are increased, as in obese subjects (21Prentki M. Corkey B.E. Diabetes. 1996; 45: 273-283Crossref PubMed Scopus (0) Google Scholar, 22Prentki M. Tornheim K. Corkey B.E. Diabetologia. 1997; 40: 32-41Crossref PubMed Scopus (151) Google Scholar). The elevated intracellular LC acyl-CoA ester concentration would be expected to activate KATP channels, thereby hyperpolarizing the beta cell and inhibiting insulin secretion. It is possible, therefore, that increased KATP channel activity, induced by LC acyl-CoA esters, may contribute to the impaired insulin secretion observed in obese non-insulin-dependent diabetics.The mechanism of beta cell KATP channel activation by oleoyl-CoA differs from that of the classical potassium channel opener diazoxide in several ways. In particular, the effects of oleoyl-CoA do not require Mg2+, nor are they abolished following mild proteolysis of the inner membrane surface (19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). This suggests that oleoyl-CoA and diazoxide may act by different mechanisms. In this paper, we show that oleoyl-CoA stimulates the activity of the cloned beta cell KATP channel (Kir6.2/SUR1). We further show this effect is mediated by interaction of the acyl-CoA ester with the Kir6.2 subunit of the channel and that it is associated with a reduced sensitivity to the inhibitory effects of ATP and a decreased rate of channel rundown. Activation by oleoyl-CoA is not observed for a related member of the inward rectifier K-channel family (Kir1.1a).DISCUSSIONWe report here that oleoyl-CoA activates the cloned beta cell KATP channel (Kir6.2/SUR1) expressed in Xenopusoocytes. This suggests that the acyl-CoA interacts directly with the KATP channel, or a channel regulator that is expressed endogenously in the Xenopus oocyte, rather than with a beta cell-specific membrane component.Subunit InteractionWe found that oleoyl-CoA activated both Kir6.2/SUR1 channels and Kir6.2ΔC36 channels expressed in the absence of SUR1. This result indicates that the mechanism of acyl-CoA activation does not require the presence of the sulfonylurea receptor subunit and is thus very different from that of other KATPchannel activators, such as MgADP and diazoxide, which mediate their effects via SUR1 (8Nichols C.G. Shyng S.-L. Nestorowicz A,. Glaser B. Clement J.P., IV Gonzalez G. Aguilar-Bryan L. Permutt M.A. Bryan J. Science. 1996; 272: 1785-1787Crossref PubMed Scopus (467) Google Scholar, 9Gribble F.M. Tucker S.J. Ashcroft F.M. EMBO J. 1997; 16: 1145-1152Crossref PubMed Scopus (310) Google Scholar, 10Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 643-654Crossref PubMed Scopus (246) Google Scholar, 11Trapp S. Tucker S.J. Ashcroft F.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8872-8877Crossref PubMed Scopus (54) Google Scholar, 12Tucker S.J. Gribble F.M. Zhao C. Trapp S. Ashcroft F.M. Nature. 1997; 378: 179-183Crossref Scopus (675) Google Scholar). Our results provide an explanation for the findings of studies on the native beta cell KATP channel which have shown that the response to oleoyl-CoA was both Mg2+-independent and unimpaired by trypsinization of the inner membrane surface (19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), conditions that abolish the potentiatory action of ADP and diazoxide (28Proks P. Ashcroft F.M. Pflügers Arch. Eur. J. Physiol. 1993; 424: 63-72Crossref PubMed Scopus (37) Google Scholar, 31Ashcroft F.M. Kakei M. J. Physiol. 1989; 416: 349-367Crossref PubMed Scopus (122) Google Scholar, 32Kozlowski R.J. Hales C.N. Ashford M.L.J. Br. J. Pharmacol. 1989; 97: 1039-1050Crossref PubMed Scopus (85) Google Scholar). Oleoyl-CoA is the first compound to be shown to mediate a stimulatory effect on KATP channel activity via the Kir6.2 subunit.Although we show that SUR1 is not required for KATP channel activation by oleoyl-CoA, our results do not allow us to conclude that the compound interacts directly with the Kir6.2 subunit itself. It is possible, for example, that oleoyl-CoA interacts with the lipid membrane, or with a third protein endogenously present in bothXenopus oocytes and pancreatic beta cells that influences KATP channel activity. Direct binding of oleoyl-CoA to other proteins has been demonstrated, including those within the metabolic pathway such as the ATP/ADP translocase and the uncoupling protein (33Ruoho A.E. Woldegiorgis G. Kobayshi C. Shrago E. J. Biol. Chem. 1989; 264: 4168-4172Abstract Full Text PDF PubMed Google Scholar,34Woldegiorgis G. Duff T. Contreras L. Shrago E. Ruoho A.E. Biochem. Biophys. Res. Commun. 1989; 161: 502-507Crossref PubMed Scopus (8) Google Scholar) and with transcription factors (35Hertz R. Magenheim J. Berman I. Bar-Tana J. Nature. 1997; 392: 512-516Crossref Scopus (452) Google Scholar). Binding studies are therefore now required to determine whether oleoyl-CoA directly binds to Kir6.2.Altered ATP SensitivityOur results demonstrate that oleoyl-CoA reduces the sensitivity of Kir6.2/SUR1 and Kir6.2ΔC36 channels to ATP. There are a number of possible explanations for this finding. First, the acyl-CoA might compete with ATP for its binding site. Second, oleoyl-CoA might allosterically affect the conformation, and thereby the affinity, of the ATP-binding site. Third, oleoyl-CoA might indirectly alter the apparent ATP sensitivity by affecting the single-channel kinetics; for example, if the ATP-inhibited state were only accessible when the channel were closed, an increase in the open probability would necessarily decrease the channel ATP sensitivity (36Tucker S.J. Gribble F.M. Proks P. Trapp S. Ryder T.J. Haug T. Reimann F. Ashcroft F.M. EMBO J. 1998; 17: 3290-3296Crossref PubMed Scopus (198) Google Scholar, 37Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 141-153Crossref PubMed Scopus (128) Google Scholar). Because oleoyl-CoA does in fact alter the single-channel kinetics and shifts the gating of the channel toward the open state, the latter possibility may contribute, at least in part, to the reduced ATP-sensitivity.Other K-channels and Lipid EffectorsThe anionic phospholipid PIP2 interacts with native cardiac and beta cell KATP channels to enhance their activity (38Hilgemann D.W. Ball R. Science. 1996; 273: 956-959Crossref PubMed Scopus (557) Google Scholar, 39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). Activation of Kir6.2/SUR1 currents by PIP2 has also been reported (39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). However, the properties of PIP2 activation are not identical to those of oleoyl-CoA, because the effect of PIP2 was instantaneous and the compound also activated Kir1.1a (39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). This makes it less likely that the two compounds interact with the channel in exactly the same way.In contrast to the native and cloned beta cell KATPchannel, the mitochondrial KATP channel is inhibited by oleoyl-CoA (Ki, 80 nm; Ref. 40Pauceek P. Yarov-Yarovoy V. Sun X. Garlid K. J. Biol. Chem. 1996; 271: 32084-32088Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The molecular identity of this channel has not been determined, but our data suggest either that the pore-forming subunit is unlikely to be Kir6.2 or that an additional inhibitory effect of oleoyl-CoA is mediated through a second subunit.Physiological ImplicationsOur results indicate that oleoyl-CoA interacts with the Kir6.2, rather than the SUR1, subunit of the KATP channel. Kir6.2 is expressed in a number of tissues, including heart, skeletal muscle, and certain brain regions (13Inagaki N. Gonoi T. Clement J.P. Namba N. Inazawa J. Gonzalez G. Aguilar-Bryan L. Seino S. Bryan J. Science. 1995; 270: 1166-1169Crossref PubMed Scopus (1607) Google Scholar, 15Sakura H. Ämmälä C. Smith P.A. Gribble F.M. Ashcroft F.M. FEBS Lett. 1995; 377: 338-344Crossref PubMed Scopus (402) Google Scholar, 41Karschin C. Ecke C. Ashcroft F.M. Karschin A. FEBS Lett. 1996; 401: 59-64Crossref Scopus (202) Google Scholar). It is believed to serve as the pore-forming subunit in all these tissues. Our data therefore suggest that long chain acyl-CoA esters may also influence KATP channel function, and thereby electrical activity, in tissues other than the beta cell.The increased activity, and reduced sensitivity of Kir6.2/SUR1 and Kir6.2ΔC36 to ATP, observed in the presence of oleoyl-CoA may have important physiological implications. Long-term exposure to elevated levels of circulating free fatty acids occurs in diabetes and obesity and has also been shown to increase the intracellular levels of long-chain acyl CoA esters (18Larsson O. Deeney J.T. Bränström R. Berggren P-O. Corkey B.E. J. Biol. Chem. 1996; 271: 10623-10626Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 20Prentki M. Vischer S. Glennon M.C. Regazzi R. Deeney J.T. Corkey B.E. J. Biol. Chem. 1992; 267: 5802-5810Abstract Full Text PDF PubMed Google Scholar). Our results suggest that this both enhances the activity of the KATP channel and renders it less sensitive to ATP, thereby producing membrane hyperpolarization and decreasing glucose-induced insulin secretion. This might contribute to the reduced sensitivity of the pancreatic beta cell to glucose observed in non-insulin-dependent diabetes mellitus. Potassium channels that are inhibited by ATP (KATPchannels)1 are found in many tissues, where they serve to couple the metabolic state of the cell to its electrical activity (1Ashcroft F.M. Annu. Rev. Neurosci. 1988; 11: 97-118Crossref PubMed Scopus (767) Google Scholar). In the pancreatic beta cell, for example, they provide the link between changes in blood glucose concentration and insulin secretion. The KATP channel sets the beta cell resting membrane potential, and its closure in response to glucose metabolism elicits membrane depolarization, activation of voltage-gated Ca2+ channels, and a rise in Ca2+ influx that stimulates insulin release (2Ashcroft F.M. Rorsman P. Prog. Biophys. Mol. Biol. 1989; 54: 87-143Crossref PubMed Scopus (945) Google Scholar). In cardiac muscle, and in brain neurons, KATP channels may be involved in the response to ischemia, whereas in smooth muscle they are important for the regulation of vascular tone (3Nichols C.G. Lederer W.J. Am. J. Physiol. 1991; 261: H1675-H1686PubMed Google Scholar, 4Quayle J.M. Nelson M.T. Standen N.B. Physiol. Rev. 1997; 77: 1165-1232Crossref PubMed Scopus (708) Google Scholar). KATP channels are formed by the physical association of four inwardly rectifying K+ channel (Kir6.2) subunits with four sulfonylurea receptor (SUR) subunits (5Clement J.P., IV Kunjilwar K. Gonzalez G. Schwanstecher M. Panten U. Aguilar-Bryan L. Bryan J. Neuron. 1997; 18: 827-838Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar, 6Inagaki N. Gonoi T. Seino S. FEBS Lett. 1997; 409: 232-236Crossref PubMed Scopus (244) Google Scholar, 7Shyng S.-L. Nichols C.G. J. Gen. Physiol. 1997; 110: 655-664Crossref PubMed Scopus (418) Google Scholar). Kir6.2 serves as an ATP-sensitive pore that is common to many types of KATPchannels. SUR is a regulatory subunit that modulates the channel gating properties, enhances the apparent ATP-sensitivity, and acts as the target for sulfonylurea drugs, K-channel openers and intracellular Mg-nucleotides, which modulate KATP channel activity (8Nichols C.G. Shyng S.-L. Nestorowicz A,. Glaser B. Clement J.P., IV Gonzalez G. Aguilar-Bryan L. Permutt M.A. Bryan J. Science. 1996; 272: 1785-1787Crossref PubMed Scopus (467) Google Scholar, 9Gribble F.M. Tucker S.J. Ashcroft F.M. EMBO J. 1997; 16: 1145-1152Crossref PubMed Scopus (310) Google Scholar, 10Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 643-654Crossref PubMed Scopus (246) Google Scholar, 11Trapp S. Tucker S.J. Ashcroft F.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8872-8877Crossref PubMed Scopus (54) Google Scholar, 12Tucker S.J. Gribble F.M. Zhao C. Trapp S. Ashcroft F.M. Nature. 1997; 378: 179-183Crossref Scopus (675) Google Scholar). It is currently believed that Kir6.2/SUR1 forms the beta cell KATP channel, Kir6.2/SUR2A forms the cardiac KATP channel, and Kir6.2/SUR2B forms the smooth muscle KATP channel (13Inagaki N. Gonoi T. Clement J.P. Namba N. Inazawa J. Gonzalez G. Aguilar-Bryan L. Seino S. Bryan J. Science. 1995; 270: 1166-1169Crossref PubMed Scopus (1607) Google Scholar, 14Inagaki N. Gonoi T. Clement J.P., IV Wang C.Z. Aguilar-Bryan L. Bryan J. Seino S. Neuron. 1996; 16: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar, 15Sakura H. Ämmälä C. Smith P.A. Gribble F.M. Ashcroft F.M. FEBS Lett. 1995; 377: 338-344Crossref PubMed Scopus (402) Google Scholar, 16Chutkow W.A. Simon M.C. Le Beau M.M. Burant C.F. Diabetes. 1996; 45: 1439-1445Crossref PubMed Scopus (225) Google Scholar, 17Isomoto S. Kondo C. Yamada M. Matsumoto S. Higashiguchi O. Horio Y. Matsuzawa Y. Kurachi Y. J. Biol. Chem. 1996; 271: 24321-24325Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). It has recently been shown that long chain (LC) acyl-CoA esters are able to activate native KATP channels in inside-out membrane patches excised from pancreatic beta cells (18Larsson O. Deeney J.T. Bränström R. Berggren P-O. Corkey B.E. J. Biol. Chem. 1996; 271: 10623-10626Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). The intracellular concentrations of LC acyl-CoA esters are predicted to vary with the metabolic state of the cell. Because long-term exposure to nonesterified fatty acids increases cellular levels of LC acyl-CoA esters in the beta cell (18Larsson O. Deeney J.T. Bränström R. Berggren P-O. Corkey B.E. J. Biol. Chem. 1996; 271: 10623-10626Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 20Prentki M. Vischer S. Glennon M.C. Regazzi R. Deeney J.T. Corkey B.E. J. Biol. Chem. 1992; 267: 5802-5810Abstract Full Text PDF PubMed Google Scholar), this finding may have implications for the regulation of insulin secretion under conditions in which nonesterified fatty acids are increased, as in obese subjects (21Prentki M. Corkey B.E. Diabetes. 1996; 45: 273-283Crossref PubMed Scopus (0) Google Scholar, 22Prentki M. Tornheim K. Corkey B.E. Diabetologia. 1997; 40: 32-41Crossref PubMed Scopus (151) Google Scholar). The elevated intracellular LC acyl-CoA ester concentration would be expected to activate KATP channels, thereby hyperpolarizing the beta cell and inhibiting insulin secretion. It is possible, therefore, that increased KATP channel activity, induced by LC acyl-CoA esters, may contribute to the impaired insulin secretion observed in obese non-insulin-dependent diabetics. The mechanism of beta cell KATP channel activation by oleoyl-CoA differs from that of the classical potassium channel opener diazoxide in several ways. In particular, the effects of oleoyl-CoA do not require Mg2+, nor are they abolished following mild proteolysis of the inner membrane surface (19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). This suggests that oleoyl-CoA and diazoxide may act by different mechanisms. In this paper, we show that oleoyl-CoA stimulates the activity of the cloned beta cell KATP channel (Kir6.2/SUR1). We further show this effect is mediated by interaction of the acyl-CoA ester with the Kir6.2 subunit of the channel and that it is associated with a reduced sensitivity to the inhibitory effects of ATP and a decreased rate of channel rundown. Activation by oleoyl-CoA is not observed for a related member of the inward rectifier K-channel family (Kir1.1a). DISCUSSIONWe report here that oleoyl-CoA activates the cloned beta cell KATP channel (Kir6.2/SUR1) expressed in Xenopusoocytes. This suggests that the acyl-CoA interacts directly with the KATP channel, or a channel regulator that is expressed endogenously in the Xenopus oocyte, rather than with a beta cell-specific membrane component.Subunit InteractionWe found that oleoyl-CoA activated both Kir6.2/SUR1 channels and Kir6.2ΔC36 channels expressed in the absence of SUR1. This result indicates that the mechanism of acyl-CoA activation does not require the presence of the sulfonylurea receptor subunit and is thus very different from that of other KATPchannel activators, such as MgADP and diazoxide, which mediate their effects via SUR1 (8Nichols C.G. Shyng S.-L. Nestorowicz A,. Glaser B. Clement J.P., IV Gonzalez G. Aguilar-Bryan L. Permutt M.A. Bryan J. Science. 1996; 272: 1785-1787Crossref PubMed Scopus (467) Google Scholar, 9Gribble F.M. Tucker S.J. Ashcroft F.M. EMBO J. 1997; 16: 1145-1152Crossref PubMed Scopus (310) Google Scholar, 10Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 643-654Crossref PubMed Scopus (246) Google Scholar, 11Trapp S. Tucker S.J. Ashcroft F.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8872-8877Crossref PubMed Scopus (54) Google Scholar, 12Tucker S.J. Gribble F.M. Zhao C. Trapp S. Ashcroft F.M. Nature. 1997; 378: 179-183Crossref Scopus (675) Google Scholar). Our results provide an explanation for the findings of studies on the native beta cell KATP channel which have shown that the response to oleoyl-CoA was both Mg2+-independent and unimpaired by trypsinization of the inner membrane surface (19Bränström R. Corkey B.E. Berggren P-O. Larsson O. J. Biol. Chem. 1997; 272: 17390-17394Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), conditions that abolish the potentiatory action of ADP and diazoxide (28Proks P. Ashcroft F.M. Pflügers Arch. Eur. J. Physiol. 1993; 424: 63-72Crossref PubMed Scopus (37) Google Scholar, 31Ashcroft F.M. Kakei M. J. Physiol. 1989; 416: 349-367Crossref PubMed Scopus (122) Google Scholar, 32Kozlowski R.J. Hales C.N. Ashford M.L.J. Br. J. Pharmacol. 1989; 97: 1039-1050Crossref PubMed Scopus (85) Google Scholar). Oleoyl-CoA is the first compound to be shown to mediate a stimulatory effect on KATP channel activity via the Kir6.2 subunit.Although we show that SUR1 is not required for KATP channel activation by oleoyl-CoA, our results do not allow us to conclude that the compound interacts directly with the Kir6.2 subunit itself. It is possible, for example, that oleoyl-CoA interacts with the lipid membrane, or with a third protein endogenously present in bothXenopus oocytes and pancreatic beta cells that influences KATP channel activity. Direct binding of oleoyl-CoA to other proteins has been demonstrated, including those within the metabolic pathway such as the ATP/ADP translocase and the uncoupling protein (33Ruoho A.E. Woldegiorgis G. Kobayshi C. Shrago E. J. Biol. Chem. 1989; 264: 4168-4172Abstract Full Text PDF PubMed Google Scholar,34Woldegiorgis G. Duff T. Contreras L. Shrago E. Ruoho A.E. Biochem. Biophys. Res. Commun. 1989; 161: 502-507Crossref PubMed Scopus (8) Google Scholar) and with transcription factors (35Hertz R. Magenheim J. Berman I. Bar-Tana J. Nature. 1997; 392: 512-516Crossref Scopus (452) Google Scholar). Binding studies are therefore now required to determine whether oleoyl-CoA directly binds to Kir6.2.Altered ATP SensitivityOur results demonstrate that oleoyl-CoA reduces the sensitivity of Kir6.2/SUR1 and Kir6.2ΔC36 channels to ATP. There are a number of possible explanations for this finding. First, the acyl-CoA might compete with ATP for its binding site. Second, oleoyl-CoA might allosterically affect the conformation, and thereby the affinity, of the ATP-binding site. Third, oleoyl-CoA might indirectly alter the apparent ATP sensitivity by affecting the single-channel kinetics; for example, if the ATP-inhibited state were only accessible when the channel were closed, an increase in the open probability would necessarily decrease the channel ATP sensitivity (36Tucker S.J. Gribble F.M. Proks P. Trapp S. Ryder T.J. Haug T. Reimann F. Ashcroft F.M. EMBO J. 1998; 17: 3290-3296Crossref PubMed Scopus (198) Google Scholar, 37Shyng S.L. Ferrigni T. Nichols C.G. J. Gen. Physiol. 1997; 110: 141-153Crossref PubMed Scopus (128) Google Scholar). Because oleoyl-CoA does in fact alter the single-channel kinetics and shifts the gating of the channel toward the open state, the latter possibility may contribute, at least in part, to the reduced ATP-sensitivity.Other K-channels and Lipid EffectorsThe anionic phospholipid PIP2 interacts with native cardiac and beta cell KATP channels to enhance their activity (38Hilgemann D.W. Ball R. Science. 1996; 273: 956-959Crossref PubMed Scopus (557) Google Scholar, 39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). Activation of Kir6.2/SUR1 currents by PIP2 has also been reported (39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). However, the properties of PIP2 activation are not identical to those of oleoyl-CoA, because the effect of PIP2 was instantaneous and the compound also activated Kir1.1a (39Fan Z. Makielski J.C. J. Biol. Chem. 1997; 272: 5388-5395Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). This makes it less likely that the two compounds interact with the channel in exactly the same way.In contrast to the native and cloned beta cell KATPchannel, the mitochondrial KATP channel is inhibited by oleoyl-CoA (Ki, 80 nm; Ref. 40Pauceek P. Yarov-Yarovoy V. Sun X. Garlid K. J. Biol. Chem. 1996; 271: 32084-32088Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). The molecular identity of this channel has not been determined, but our data suggest either that the pore-forming subunit is un" @default.
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• W2093537983 title "Mechanism of Cloned ATP-sensitive Potassium Channel Activation by Oleoyl-CoA" @default.
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