The Kinetic and Physical Basis of KATP Channel Gating: Toward a Unified Molecular Understanding

Enkvetchakul, Decha; Loussouarn, Gildas; Makhina, Elena; Shyng, Show Ling; Nichols, Colin G.

doi:10.1016/s0006-3495(00)76779-8

Cited by 158 publications

(280 citation statements)

References 56 publications

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“…In contrast to nucleoside diphosphates, ATP does not affect burst duration, but solely increases the average time spent in interburst closed states (27,28), suggesting exclusive binding to these states. E23K-induced reduction of the time spent in interburst closure should thus lower the amount of bound ATP.…”

Section: Discussionmentioning

confidence: 77%

The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates

et al. 2002

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E23K, a common polymorphism in the pore-forming subunit K IR 6.2 of pancreatic ␤-cell ATP-sensitive K ؉ (K ATP ) channels, is functionally relevant and thus might play a major role in the pathophysiology of common type 2 diabetes. In this study, we show that in the simultaneous presence of activatory and inhibitory nucleotides, the polymorphism exerts opposite effects on the potencies of these modulators: channel opening through nucleoside diphosphates is facilitated, whereas sensitivity toward inhibition through ATP is slightly decreased. The results support the conclusion that E23K predisposes to type 2 diabetes by changing the channel's response to physiological variation of cytosolic nucleotides, resulting in K ATP overactivity and discrete inhibition of insulin release. T ype 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors (1). Genes encoding for key components of insulin secretion and glucose metabolism pathways have been widely considered as targets for defects in type 2 diabetes (2). One of these key proteins is the ATPsensitive K ϩ channel (K ATP channel) in pancreatic ␤-cells. This channel critically controls insulin secretion by coupling metabolism to electrical activity (3). The ␤-cell channel is assembled with a tetradimeric stoichiometry from two structurally distinct subunits: the inwardly rectifying potassium channel subunit (K IR 6.2), which forms the pore, and the regulatory sulfonylurea receptor subunit 1 (SUR1) (4,5). While hypoglycemic sulfonylureas (e.g., glibenclamide) exert their effects on channel activity by interacting with SUR1, there is strong evidence that the receptor site for inhibitory ATP is located on K IR 6.2.E23K (substitution of a lysine [K] for a glutamic acid [E] in position 23) is one of three common missense single nucleotide polymorphisms (SNPs) that have been observed in K IR 6.2 (E23K, L270V, I337V) (6 -10). Recently, we presented evidence that this polymorphism predisposes to type 2 diabetes by inducing overactivity of K ATP channels in the pancreatic ␤-cell (11). In particular, E23K markedly affects channel gating, significantly reducing the time spent in long interburst closed states and thereby producing an evident increase of spontaneous open probability (P O ). Consistent with the idea that nucleotide-induced channel inhibition results from interaction with the interburst closed states (12,13), sensitivity toward inhibitory ATP 4Ϫ was found to be decreased (11).In intact cells, however, other factors besides inhibitory ATP contribute to regulation of channel activity, with ADP presumably representing the most important of these additional parameters (14). ADP has at least three distinct effects on channel activity: 1) Free ADP 3Ϫ inhibits channel activity in isolated patches with a potency slightly lower than that of ATP 4Ϫ (half-maximal inhibitory concentration value [IC 50 ] 49 vs. 8.9 mol/l, respectively) (11,15). 2) The Mg 2ϩ complex of ADP (MgADP) per se poten...

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Section: Discussionmentioning

confidence: 77%

The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates

et al. 2002

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“…Thus, the P O (0) of homomeric channels containing the R201C mutation was not significantly different from wild-type, whereas that of homQ52R and homV59G channels was substantially greater (Table 1). It is well documented that an increase in P O (0) reduces the ability of ATP to close the K ATP channel (30,31). Thus, mutations at residue 201, which lies within the putative ATP-binding site (8), probably act by reducing ATP binding per se, whereas the Q52R and V59G mutations appear to decrease ATP sensitivity indirectly, by favoring the open conformation of the channel.…”

Section: Pearson and A T Hattersley Personal Communication)mentioning

confidence: 99%

Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features

Proks

Antcliff

Lippiat

et al. 2004

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

220

295

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Inwardly rectifying potassium channels (Kir channels) control cell membrane K ؉ fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (KATP) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2͞sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell K ATP currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K ATP currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased KATP currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger KATP currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype. potassium channel ͉ KATP channel ͉ KCNJ11 ͉ ATP-binding site

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“…First, ATP and PIP 2 might bind to overlapping sites, and secondly, PIP 2 modulates ATP inhibition allosterically by interaction with basic residues in regions that are critical for the gating mechanism that links ATP binding to channel closure. Both alternatives have been put forward recently (27)(28)(29). As an argument against physically overlapping binding sites it has been pointed out that mutations in the C terminus that affected PIP 2 binding in the most cases did not change ATP inhibition (19).…”

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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The Kinetic and Physical Basis of KATP Channel Gating: Toward a Unified Molecular Understanding

Cited by 158 publications

References 56 publications

The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates

The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates

Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features

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

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