Long-chain acyl-CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of KATP channels by the same mechanism

Schulze, Dirk; Rapedius, Markus; Krauter, Tobias; Baukrowitz, Thomas

doi:10.1113/jphysiol.2003.047035

Cited by 70 publications

(23 citation statements)

References 31 publications

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“…4C). As reported in many previous studies, both PIP 2 and LC-CoA increased WT channel activity and rendered channels less sensitive to ATP inhibition [5], [7], [29], [40]–[43].…”

Section: Resultssupporting

confidence: 81%

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A Kir6.2 Pore Mutation Causes Inactivation of ATP-Sensitive Potassium Channels by Disrupting PIP2-Dependent Gating

2013

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In the absence of intracellular nucleotides, ATP-sensitive potassium (KATP) channels exhibit spontaneous activity via a phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent gating process. Previous studies show that stability of this activity requires subunit-subunit interactions in the cytoplasmic domain of Kir6.2; selective mutagenesis and disease mutations at the subunit interface result in time-dependent channel inactivation. Here, we report that mutation of the central glycine in the pore-lining second transmembrane segment (TM2) to proline in Kir6.2 causes KATP channel inactivation. Unlike C-type inactivation, a consequence of selectivity filter closure, in many K+ channels, the rate of inactivation in G156P channels was insensitive to changes in extracellular ion concentrations or ion species fluxing through the pore. Instead, the rate of G156P inactivation decreased with exogenous application of PIP2 and increased when PIP2-channel interaction was inhibited with neomycin or poly-L-lysine. These findings indicate the G156P mutation reduces the ability of PIP2 to stabilize the open state of KATP channels, similar to mutations in the cytoplasmic domain that produce inactivation. Consistent with this notion, when PIP2-dependent open state stability was substantially increased by addition of a second gain-of-function mutation, G156P inactivation was abolished. Importantly, bath application and removal of Mg2+-free ATP or a nonhydrolyzable analog of ATP, which binds to the cytoplasmic domain of Kir6.2 and causes channel closure, recover G156P channel from inactivation, indicating crosstalk between cytoplasmic and transmembrane domains. The G156P mutation provides mechanistic insight into the structural and functional interactions between the pore and cytoplasmic domains of Kir6.2 during gating.

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“…4C). As reported in many previous studies, both PIP 2 and LC-CoA increased WT channel activity and rendered channels less sensitive to ATP inhibition [5], [7], [29], [40]–[43].…”

Section: Resultssupporting

confidence: 81%

“…4A). Long-chain CoA (LC-CoA; oleoyl CoA was used in this study) which also activates K ATP via a mechanism similar to PIP 2 [40], [41] likewise antagonized channel inactivation (Fig. 4B).…”

Section: Resultsmentioning

confidence: 99%

A Kir6.2 Pore Mutation Causes Inactivation of ATP-Sensitive Potassium Channels by Disrupting PIP2-Dependent Gating

2013

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“…A clear picture of the structure of the K ATP channel may hold the key to determining the precise mechanism by which LC-CoAs alter channel activity and the way in which the E23K polymorphism affects this process. The recent crystallization of related inwardrectifier potassium channels KirBac1.1 and GIRK (Kuo et al 2003;Nishida and MacKinnon 2002) may facilitate our understanding of the actions of polymorphisms on the binding of channel ligands such as ATP, PIP 2 , and LC-CoAs, three molecules that act directly on the Kir6.2 subunit of the K ATP channel (Schulze et al 2003b). Although neither of these crystal structures currently includes the distal N-terminus (and therefore the E23 residue), significant progress is being made and may soon lead to a more complete model of the K ATP channel at the molecular level.…”

Section: The Effects Of Lc-coas On K Atp Channel Functionmentioning

confidence: 97%

Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes

2004

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The ATP-sensitive potassium (KATP) channel couples membrane excitability to cellular metabolism and is a critical mediator in the process of glucose-stimulated insulin secretion. Increasing numbers of KATP channel polymorphisms are being described and linked to altered insulin secretion indicating that genes encoding this ion channel could be susceptibility markers for type-2 diabetes. Genetic variation of KATP channels may result in altered beta-cell electrical activity, glucose homeostasis, and increased susceptibility to type-2 diabetes. Of particular interest is the Kir6.2 E23K polymorphism, which is linked to increased susceptibility to type-2 diabetes in Caucasian populations and may also be associated with weight gain and obesity, both of which are major diabetes risk factors. This association highlights the potential contribution of both genetic and environmental factors to the development and progression of type-2 diabetes. In addition, the common occurrence of the E23K polymorphism in Caucasian populations may have conferred an evolutionary advantage to our ancestors. This review will summarize the current status of the association of KATP channel polymorphisms with type-2 diabetes, focusing on the possible mechanisms by which these polymorphisms alter glucose homeostasis and offering insights into possible evolutionary pressures that may have contributed to the high prevalence of KATP channel polymorphisms in the Caucasian population.

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“…Both PIP 2 and LC-CoAs interact with Kir6.2 via similar mechanisms to increase channel open probability and antagonize ATP inhibition (Schulze et al, 2003). Mutagenesis studies indicate that PIP 2 and ATP may have overlapping but non-identical binding sites in Kir6.2 (Shyng et al, 2000; Cukras et al, 2002a,b; Antcliff et al, 2005).…”

Section: Gating Regulation Of Katp Channelsmentioning

confidence: 99%

Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels

et al. 2013

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ATP-sensitive potassium (KATP) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, KATP channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The β-cell KATP channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, KATP channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct KATP channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed.

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Long-chain acyl-CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of KATP channels by the same mechanism

Cited by 70 publications

References 31 publications

A Kir6.2 Pore Mutation Causes Inactivation of ATP-Sensitive Potassium Channels by Disrupting PIP2-Dependent Gating

A Kir6.2 Pore Mutation Causes Inactivation of ATP-Sensitive Potassium Channels by Disrupting PIP2-Dependent Gating

Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes

Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels

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