Cytoplasmic Unsaturated Free Fatty Acids Inhibit Atp-Dependent Gating of the G Protein–Gated K+ Channel

Kim, Dong‐Hee; Pleumsamran, Apisate

doi:10.1085/jgp.115.3.287

Cited by 32 publications

(31 citation statements)

References 52 publications

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“…By contrast, similar concentrations of unsaturated fatty acids, including arachidonic acid, inhibit the ATP-dependent opening of cardiac and neuronal G-protein-gated potassium channels (K Ach ). Kim and Pleumsamran have argued clearly for the physiological relevance of this process (40). Briefly, they have shown that a lipid extractable from cell cytosol has inhibitory activity and that the biological response is mimicked by unsaturated fatty acids; these have activity only when applied on the cytosolic side of the cell membrane.…”

Section: Bioactivities Of Arachidonic Acidmentioning

confidence: 99%

Arachidonic acid as a bioactive molecule

2001

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Section: Bioactivities Of Arachidonic Acidmentioning

confidence: 99%

Arachidonic acid as a bioactive molecule

2001

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“…The poor reversibility of oleate was probably secondary to its slow rate of washout from the patch lipid bilayer. 25 Modulation of the cardiac K ATP channel is not restricted to oleoyl-CoA and oleate. We found that 1 mol/L palmitoleoyl-CoA (C16:1 acyl group) also activated single K ATP channels after partial rundown and reduced ATP sensitivity (nϭ4; not shown).…”

Section: Effects Of Free Fatty Acids On Cardiac K Atp Channelsmentioning

confidence: 99%

Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to K _ATP Channels in the Heart

Liu

Hanley

Ray

et al. 2001

Circulation Research

102

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Abstract-ATP-sensitive K (K ATP ) channels are inhibited by cytosolic ATP, a defining property that implicitly links these channels to cellular metabolism. Here we report a direct link between fatty acid metabolism and K ATP channels in cardiac muscle cells. Long-chain (LC) acyl-coenzyme A (CoA) esters are synthesized from fatty acids and serve as the principal metabolic substrates of the heart. We have studied the effects of LC acyl-CoA esters and LC fatty acids on K ATP channels of isolated guinea pig ventricular myocytes and compared them with the effects of phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Application of oleoyl-CoA (0.2 or 1 mol/L), a naturally occurring acyl-CoA ester, to the cytosolic side of excised patches completely prevented rundown of K ATP channels, but not of Kir2 channels. The open probability of K ATP channels measured in the presence of oleoyl-CoA or PIP 2 was voltage dependent, increasing with depolarization. Oleoyl-CoA greatly reduced the ATP sensitivity of K ATP channels. At a concentration of 2 mol/L, oleoyl-CoA increased the half-maximal inhibitory concentration of ATP Ͼ200-fold. The time course of the decrease in ATP sensitivity was much faster during application of oleoyl-CoA than during application of PIP 2 . The effects of PIP 2 , but not of oleoyl-CoA, were inhibited by increasing Ca 2ϩ to 1 mmol/L. Oleate (C18:1; 10 mol/L), the precursor of oleoyl-CoA, inhibited K ATP channels activated by oleoyl-CoA. Palmitoleoyl-CoA and palmitoleate (C16:1) exerted similar reciprocal effects. These findings indicate that LC fatty acids and their CoA-linked derivatives may be key physiological modulators of K ATP channel activity in the heart. (Circ Res. 2001;88:918-924.) Key Words: free fatty acids Ⅲ acyl-CoA esters Ⅲ PIP 2 Ⅲ K ATP channels A TP-sensitive potassium (K ATP ) channels link energy metabolism with the electrical activity of the heart. [1][2][3] This link is functionally important during hypoxia or ischemia. Any imbalance in the ratio between energy supply through coronary arteries and energy expenditure by cardiac myocytes will indirectly modulate electrical activity, because a change in the ATP/ADP ratio, together with acidosis, promotes activation of K ATP channels. 4 -6 By increasing K ϩ efflux and shortening the duration of the action potential, K ATP channel activation reduces transsarcolemmal Ca 2ϩ influx and thereby the energy costs of Ca 2ϩ -ATPases and actomyosin-ATPase. Hence, in the face of reduced energy supply, K ATP channels may provide a means to decrease cytosolic energy demand.We report here a direct effect of long-chain (LC) acylcoenzyme A (CoA) esters and fatty acids on the activity of K ATP channels in isolated cardiac myocytes. We have shown that LC acyl-CoA esters facilitate the opening of K ATP channels by reducing their ATP sensitivity. The precursors of LC acyl-CoA esters, LC fatty acids, were found to inhibit K ATP channels. The reciprocal effects of free fatty acids and acyl-CoA esters on K ATP channels represent a novel link between energy metab...

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“…Arachidonic acid and its metabolites modulate several ion channels, including Kir3.1 and Kir3.4 heteromultimers in cardiac myocytes (16). Unsaturated free fatty acids such as oleic, linoleic, and arachidonic acids inhibit Kir3.1 and Kir3.4 heteromultimers by blocking ATP-dependent gating in atrial cells (7). We previously showed that arachidonic acid inhibits the potassium channel response to the mu opioid agonist DAMGO in Xenopus oocytes expressing MOR and Kir3 heteromultimers (17).…”

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confidence: 99%

Eicosanoids Inhibit the G-protein-gated Inwardly Rectifying Potassium Channel (Kir3) at the Na+/PIP2 Gating Site

Rogalski

Chavkin

2001

Journal of Biological Chemistry

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We previously showed that activation of the human endothelin A receptor (HETAR) by endothelin-1 (Et-1) selectively inhibits the response to mu opioid receptor (MOR) activation of the G-protein-gated inwardly rectifying potassium channel (Kir3). The Et-1 effect resulted from PLA2 production of an eicosanoid that inhibited Kir3. In this study, we show that Kir3 inhibition by eicosanoids is channel subunit-specific, and we identify the site within the channel required for arachidonic acid sensitivity. Activation of the G-protein-coupled MOR by the selective opioid agonist D-Ala 2 Glyol, enkephalin, released G␤␥ that activated Kir3. The response to MOR activation was significantly inhibited by Et-1 activation of HETAR in homomeric channels composed of either Kir3.2 or Kir3.4. In contrast, homomeric channels of Kir3.1 were substantially less sensitive. Domain deletion and channel chimera studies suggested that the sites within the channel required for Et-1-induced inhibition were within the region responsible for channel gating. Mutation of a single amino acid in the homomeric Kir3.1 to produce Kir3.1(F137S)(N217D) dramatically increased the channel sensitivity to arachidonic acid and Et-1 treatment. Complementary mutation of the equivalent amino acid in Kir3.4 to produce Kir3.4(S143T)(D223N) significantly reduced the sensitivity of the channel to arachidonic acid-and Et-1-induced inhibition. The critical aspartate residue required for eicosanoid sensitivity is the same residue required for Na ؉ regulation of PIP 2 gating. The results suggest a model of Kir3 gating that incorporates a series of regulatory steps, including G␤␥, PIP 2 , Na ؉ , and arachidonic acid binding to the channel gating domain.

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Cytoplasmic Unsaturated Free Fatty Acids Inhibit Atp-Dependent Gating of the G Protein–Gated K+ Channel

Cited by 32 publications

References 52 publications

Arachidonic acid as a bioactive molecule

Arachidonic acid as a bioactive molecule

Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to K _ATP Channels in the Heart

Eicosanoids Inhibit the G-protein-gated Inwardly Rectifying Potassium Channel (Kir3) at the Na+/PIP2 Gating Site

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Cytoplasmic Unsaturated Free Fatty Acids Inhibit Atp-Dependent Gating of the G Protein–Gated K+ Channel

Cited by 32 publications

References 52 publications

Arachidonic acid as a bioactive molecule

Arachidonic acid as a bioactive molecule

Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to K ATP Channels in the Heart

Eicosanoids Inhibit the G-protein-gated Inwardly Rectifying Potassium Channel (Kir3) at the Na+/PIP2 Gating Site

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Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to K _ATP Channels in the Heart