Phospholipids as Modulators of K<sub>ATP</sub> Channels: Distinct Mechanisms for Control of Sensitivity to Sulphonylureas,  K<sup>+</sup> Channel Openers, and ATP

Krauter, Tobias; Ruppersberg, J. P.; Baukrowitz, Thomas

doi:10.1124/mol.59.5.1086

Cited by 64 publications

(59 citation statements)

References 42 publications

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“…1 E and F), activated the channels in a reversible manner. The effectiveness of PI(4,5)P 2 , PI(3,4)P 2 , and PI(3,4,5)P 3 was very similar, consistent with previous reports (7,10,17). Oleoyl-CoA (10 M) also activated Kir6.2-SUR2A channels ( Fig.…”

Section: Resultssupporting

confidence: 91%

“…The activation of K ATP channels by phosphoinositides has been reported to be nonspecific, depending only on the number of charges in the lipid head-group (7,10,11,17). LC acyl-CoA activates native cardiac (22) and pancreatic (23) K ATP channels, as well as recombinant Kir6.2⌬36 channels (21).…”

Section: Resultsmentioning

confidence: 99%

“…GIRK (Kir3.x) channels (13,15), and ROMK1 (Kir1.1) channels (16) were reported to be activated by PI(4,5)P 2 , PI(3,4,5)P 3 , and PI(3,4)P 2 , and to a lesser extent by PI(4)P (13). K ATP channels were shown to be activated not only by PI(4,5)P 2 , but also by PI(3,4,5)P 3 (7) and PI(3,4)P 2 (17). When applied at higher concentrations, PI(4)P (7,10,11), phosphatidylinositol (PI) (11), and phosphatidic acid (18) could activate these channels.…”

mentioning

confidence: 95%

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Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Rohács

Lopes

Jin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

194

230

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Phosphoinositides are critical regulators of ion channel and transporter activity. Defects in interactions of inwardly rectifying potassium (Kir) channels with phosphoinositides lead to disease. ATP-sensitive K ؉ channels (KATP) are unique among Kir channels in that they serve as metabolic sensors, inhibited by ATP while stimulated by long-chain (LC) acyl-CoA. Here we show that KATP are the least specific Kir channels in their activation by phosphoinositides and we demonstrate that LC acyl-CoA activation of these channels depends on their low phosphoinositide specificity. We provide a systematic characterization of phosphoinositide specificity of the entire Kir channel family expressed in Xenopus oocytes and identify molecular determinants of such specificity. We show that mutations in the Kir2.1 channel decreasing phosphoinositide specificity allow activation by LC acyl-CoA. Our data demonstrate that differences in phosphoinositide specificity determine the modulation of Kir channel activity by distinct regulatory lipids.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 95%

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Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Rohács

Lopes

Jin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

194

230

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“…The predicted effect of P O on the concentration-response curve is illustrated in Fig. 2E, and resembles that found experimentally with increasing concentrations of PIP 2 , which also increases P O (29). Deletion of the NH 2 -terminus of Kir6.2 (Kir6.2⌬N) results in an increase in the channel P O and a concomitant reduction in tolbutamide block when Kir6.2⌬N is coexpressed with SUR1 (25).…”

Section: Sulfonylurea-bound Channels Can Still Opensupporting

confidence: 77%

Sulfonylurea Stimulation of Insulin Secretion

et al. 2002

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Sulfonylureas are widely used to treat type 2 diabetes because they stimulate insulin secretion from pancreatic ␤-cells. They primarily act by binding to the SUR subunit of the ATP-sensitive potassium (K ATP ) channel and inducing channel closure. However, the channel is still able to open to a limited extent when the drug is bound, so that high-affinity sulfonylurea inhibition is not complete, even at saturating drug concentrations. K ATP channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of different SUR subunits that confer different drug sensitivities. Thus tolbutamide and gliclazide block channels containing SUR1 (␤-cell type), but not SUR2 (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. This difference has been exploited to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea block is decreased by mutations or agents (e.g., phosphatidylinositol bisphosphate) that increase K ATP channel open probability. We now propose a kinetic model that explains this effect in terms of changes in the channel open probability and in the transduction between the drug-binding site and the channel gate. We also clarify the mechanism by which MgADP produces an apparent increase of sulfonylurea efficacy on channels containing SUR1 (but not SUR2). Diabetes 51 (Suppl. 3):S368 -S376, 2002

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“…In electrophysiological experiments, neomycin was shown to reverse the effects of PIP 2 on K ATP channels causing inhibition of channel activity and reduction of ATP sensitivity (11,25). Thus, the neomycin sensitivity of a Kir channel might be a measure of its PIP 2 affinity.…”

Section: Arg-54 In the N Terminus Of Kir62 Is A Major Determinant Fomentioning

confidence: 99%

Phosphatidylinositol 4,5-Bisphosphate (PIP2) Modulation of ATP and pH Sensitivity in Kir Channels

Schulze¹,

Krauter²,

Fritzenschaft

et al. 2003

Journal of Biological Chemistry

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Phosphatidylinositol polyphosphates (PIPs) are potent modulators of Kir channels. Previous studies have implicated basic residues in the C terminus of Kir6.2 channels as interaction sites for the PIPs. Here we examined the role of the N terminus and identified an arginine (Arg-54) as a major determinant for PIP 2 modulation of ATP sensitivity in K ATP channels. Mutation of Arg-54 to the neutral glutamine (R54Q) and, in particular, to the negatively charged glutamate (R54E) impaired PIP 2 modulation of ATP inhibition, while mutation to lysine (R54K) had no effect. These data suggest that electrostatic interactions between PIP 2 and Arg-54 are an essential step for the modulation of ATP sensitivity. This N-terminal PIP 2 site is highly conserved in Kir channels with the exception of the pH-gated channels Kir1.1, Kir4.1, and Kir5.1 that contain a neutral residue at the corresponding positions. Introduction of an arginine at this position in Kir1.1 channels rendered the N-terminal PIP 2 site functional largely increasing the PIP 2 affinity. Moreover, Kir1.1 channels lose the ability to respond to physiological changes of the intracellular pH. These results explain the need of a silent N-terminal PIP 2 site in pH-gated channels and highlight the N terminus as an important region for PIP 2 modulation of Kir channel gating.Kir channels are a superfamily of eukaryotic channel proteins that are expressed in many tissues and responsible for important physiological processes such as cell excitability, insulin secretion, K ϩ homeostasis, vascular tone, and regulation of the heart rate. Four subunits assemble to a channel. Each subunit contains two transmembrane segments with cytoplasmic N-and C-terminal domains and a connecting loop forming the pore (1). Some members of the Kir channel family are endowed with gating mechanisms such as ATP gating (K ATP channels) (2) and pH gating (Kir1.1 and Kir4.1 channels) (3). These gating mechanisms are central for the diverse functions of Kir channels in physiology and the understanding of the related pathophysiology. Kir1, Kir4, and Kir5 channels, that are predominantly expressed in epithelia, are exquisitely sensitive to changes in intracellular pH in the physiological range (3-5). This pH sensitivity is mediated by the protonation of a lysine in the N terminus (Lys-80 in Kir1.1) that induces closure of the channel's pore by an allosteric mechanism (pH gating) (3, 6). Even small changes in the pH sensitivity can cause severe kidney defects such as the Bartter syndrome (3), highlighting the physiological importance of proper pH gating in Kir1.1 channels. Kir6 channels display a very ubiquitous expression pattern and, in coassembly with the sulfonylurea receptor (SUR), 1 represent the ATP-sensitive K ϩ channels (K ATP channels) (7). Intracellular ATP closes K ATP channels by binding to the Kir6.2 subunits (ATP gating), whereas the SURs act as regulatory subunits endowing the channel with sensitivity to MgADP and pharmacological compounds. The ATP/ADP dependence of K ATP channels couple...

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Phospholipids as Modulators of K_ATP Channels: Distinct Mechanisms for Control of Sensitivity to Sulphonylureas, K⁺ Channel Openers, and ATP

Cited by 64 publications

References 42 publications

Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Sulfonylurea Stimulation of Insulin Secretion

Phosphatidylinositol 4,5-Bisphosphate (PIP2) Modulation of ATP and pH Sensitivity in Kir Channels

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Phospholipids as Modulators of KATP Channels: Distinct Mechanisms for Control of Sensitivity to Sulphonylureas, K+ Channel Openers, and ATP

Cited by 64 publications

References 42 publications

Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Specificity of activation by phosphoinositides determines lipid regulation of Kir channels

Sulfonylurea Stimulation of Insulin Secretion

Phosphatidylinositol 4,5-Bisphosphate (PIP2) Modulation of ATP and pH Sensitivity in Kir Channels

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Product

Resources

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Phospholipids as Modulators of K_ATP Channels: Distinct Mechanisms for Control of Sensitivity to Sulphonylureas, K⁺ Channel Openers, and ATP