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Genetic predisposition and bioinformatics analysis of ATP-sensitive potassium channels polymorphisms with the risks of elevated apolipoprotein B serum levels and its related arteriosclerosis cardiovascular disease.

ABSTRACT: Serum concentration of apolipoprotein B (Apo B) is causally associated with arteriosclerosis cardiovascular disease (ASCVD) risk. Whether ATP-sensitive potassium channels (KATP) variants predict the risk of increased Apo B concentration (≥ 80 mg/dL) and related ASCVD remain less clear. We recruited 522 subjects with elevated Apo B concentration (≥ 80 mg/dL) and 522 counterpart subjects (< 80 mg/dL) from South China to assess the associations of KATP variants (rs11046182, rs78148713, rs145456027 and rs147265929) with the risks of increased Apo B serum concentration (≥ 80 mg/dL), carotid artery stenosis (CAS) ≥ 50% and new-onset ischemic stroke (IS). Our results showed that only KATP SNP rs11046182 (GG genotype) was associated with increased risk of Apo B ≥ 80 mg/dL (adjusted OR=2.17, P<0.001) and CAS ≥ 50% (adjusted OR=2.63, P=0.011). After median 50.6-months follow-up, subjects carrying GG genotype of rs11046182 were associated with higher risk of new-onset IS (adjusted HR=2.24, P=0.024). Further, the exosome-derived microRNAs (exo-miRs) expression profile was identified by next-generation sequencing. 41 exo-miRs were significantly differentially expressed under cross-talk status between high Apo B level (≥ 80 mg/dL) and KATP rs11046182. Our study demonstrated that KATP variant rs11046182 was associated with higher risks of elevated serum Apo B levels and its related ASCVD, and the possible mechanism was related to specific exo-miRs expression profile of KATP rs11046182.

SUBMITTER: Liu C

PROVIDER: S-EPMC8034914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibition of ATP-sensitive potassium channels by haloperidol.

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2019-11-12 | PXD013873 | Pride

Mechanism of pharmacochaperoning in ATP-sensitive potassium channels revealed by cryo-EM

Project description:ATP-sensitive potassium (K-ATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic beta-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse K-ATP inhibitors have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of K-ATP channels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. CyanurBiotinDimercaptoPropionylSuccinimide (CBDPS) cross-linking mass spectrometry was used to partially confirm cryoEM structures.

2019-08-12 | PXD014498 | Pride

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Project description:The ATP-sensitive potassium (K(ATP)) channels which extensively distribute in diverse tissues (e.g. vascular smooth muscle, cardiac cells, and pancreas) are well-established for characteristics like vasodilatation, myocardial protection against ischemia, and insulin secretion. The aim of this review is to get insight into the novel roles of K(ATP) channels in Parkinson's disease (PD), with consideration of the specificities K(ATP) channels in the central nervous system (CNS), such as the control of neuronal excitability, action potential, mitochondrial function and neurotransmitter release.

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Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels.

Project description:Potassium channels that are inhibited by internal ATP (K(ATP) channels) provide a critical link between metabolism and cellular excitability. Protein kinase C (PKC) acts on K(ATP) channels to regulate diverse cellular processes, including cardioprotection by ischemic preconditioning and pancreatic insulin secretion. PKC action decreases the Hill coefficient of ATP binding to cardiac K(ATP) channels, thereby increasing their open probability at physiological ATP concentrations. We show that PKC similarly regulates recombinant channels from both the pancreas and heart. Surprisingly, PKC acts via phosphorylation of a specific, conserved threonine residue (T180) in the pore-forming subunit (Kir6.2). Additional PKC consensus sites exist on both Kir and the larger sulfonylurea receptor (SUR) subunits. Nonetheless, T180 controls changes in open probability induced by direct PKC action either in the absence of, or in complex with, the accessory SUR1 (pancreatic) or SUR2A (cardiac) subunits. The high degree of conservation of this site among different K(ATP) channel isoforms suggests that this pathway may have wide significance for the physiological regulation of K(ATP) channels in various tissues and organelles.

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Role of Derlin-1 protein in proteostasis regulation of ATP-sensitive potassium channels.

Project description:ATP-sensitive potassium (K(ATP)) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2 regulate insulin secretion by linking glucose metabolism with membrane potential. The number of K(ATP) channels in the plasma membrane affects the sensitivity of β-cells to glucose. Aberrant surface channel expression leads to insulin secretion disease. Previously, we have shown that K(ATP) channel proteins undergo endoplasmic reticulum (ER)-associated degradation (ERAD) via the ubiquitin-proteasome pathway, and inhibition of proteasome function results in an increase in channel surface expression. Here, we investigated whether Derlin-1, a protein involved in retrotranslocation of misfolded or misassembled proteins across the ER membrane for degradation by cytosolic proteasomes, plays a role in ERAD and, in turn, biogenesis efficiency of K(ATP) channels. We show that both SUR1 and Kir6.2 form a complex with Derlin-1 and an associated AAA-ATPase, p97. Overexpression of Derlin-1 led to a decrease in the biogenesis efficiency and surface expression of K(ATP) channels. Conversely, knockdown of Derlin-1 by RNA interference resulted in increased processing of SUR1 and a corresponding increase in surface expression of K(ATP) channels. Importantly, knockdown of Derlin-1 increased the abundance of disease-causing misfolded SUR1 or Kir6.2 proteins and even partially rescued surface expression in a mutant channel. We conclude that Derlin-1, by being involved in ERAD of SUR1 and Kir6.2, has a role in modulating the biogenesis efficiency and surface expression of K(ATP) channels. The results suggest that physiological or pathological changes in Derlin-1 expression levels may affect glucose-stimulated insulin secretion by altering surface expression of K(ATP) channels.

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