AI Article Synopsis
- Phosphatidylinositol 4,5-bisphosphate (PIP2) enhances ATP-sensitive K+ (K(ATP)) channel activity, while phospholipase C (PLC) can decrease it by hydrolyzing PIP2.
- The alpha1-adrenoceptor agonist methoxamine (MTX) was found to inhibit pinacidil-activated K(ATP) currents in a concentration-dependent manner, an effect that was prevented by the presence of the specific antagonist prazosin.
- The study suggests that stimulation of the alpha1-adrenoceptor leads to a reduction in membrane PIP2 levels, inhibiting K(ATP) channel activity, and is linked with G protein involvement and reversible changes in P
Article Abstract
Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates ATP-sensitive K+ (K(ATP)) channel activity. Because phospholipase C (PLC) hydrolyzes membrane-bound PIP2, which in turn may potentially decrease K(ATP) channel activity, we investigated the effects of the alpha1-adrenoceptor-G(q)-PLC signal transduction axis on pinacidil-activated K(ATP) channel activity in adult rat and neonatal mouse ventricular myocytes. The alpha1-adrenoceptor agonist methoxamine (MTX) reversibly inhibited the pinacidil-activated K(ATP) current in a concentration-dependent manner (IC50 20.9+/-6.6 micromol/L). This inhibition did not occur when the specific alpha1-adrenoceptor antagonist, prazosin, was present. An involvement of G proteins is suggested by the ability of GDPbetaS to prevent this response. Blockade of PLC by U-73122 (2 micromol/L) or neomycin (2 mmol/L) attenuated the MTX-induced inhibition of K(ATP) channel activity. In contrast, the MTX response was unaffected by protein kinase C inhibition or stimulation by H-7 (100 micro mol/L) or phorbol 12,13-didecanoate. The MTX-induced inhibition became irreversible in the presence of wortmannin (20 micro mol/L), an inhibitor of phosphatidylinositol-4 kinase, which is expected to prevent membrane PIP2 replenishment. In excised inside-out patch membranes, pinacidil induced a significantly rightward shift of ATP sensitivity of the channel. This phenomenon was reversed by pretreatment of myocytes with MTX. Direct visualization of PIP2 subcellular distribution using a PLCdelta pleckstrin homology domain-green fluorescent protein fusion constructs revealed reversible translocation of green fluorescent protein fluorescence from the membrane to the cytosol after alpha1-adrenoceptor stimulation. Our data demonstrate that alpha1-adrenoceptor stimulation reduces the membrane PIP2 level, which in turn inhibits pinacidil-activated K(ATP) channels.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1161/01.res.0000029971.60214.49 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Hallmarks of Quercetin Benefits as a Functional Supplementary in the Management of Diabetes Mellitus-Related Maladies: From Basic to Clinical Applications.
Curr Drug Metab
January 2025
Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
Quercetin (QE), a particular flavonoid, is well known for its medicinal effects, including anti-oxidant, hypoglycemic, and anti-inflammatory effects. In this review, the findings of QE effects on diabetes STZinduced, alloxan-induced, and its complications have been summarized with a particular focus on in vitro, in vivo, and clinical trials. Consequently, QE mediates several mechanisms, including ameliorating tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β, IL-8, and IL-10 expression, increasing insulin glucose uptake to inhibit insulin resistance.
View Article and Find Full Text PDFROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation.
Acta Neuropathol Commun
January 2025
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia.
View Article and Find Full Text PDFGenetic Structure of Hereditary Forms of Diabetes Mellitus in Russia.
Int J Mol Sci
January 2025
Endocrinology Research Center, Moscow 117292, Russia.
Analyzing the genetic architecture of hereditary forms of diabetes in different populations is a critical step toward optimizing diagnostic and preventive algorithms. This requires consideration of regional and population-specific characteristics, including the spectrum and frequency of pathogenic variants in targeted genes. As part of this study, we used a custom-designed NGS panel to screen for mutations in 28 genes associated with the pathogenesis of hereditary diabetes mellitus in 506 unrelated patients from Russia.
View Article and Find Full Text PDFLow-dose quinine targets KCNH6 to potentiate glucose-induced insulin secretion.
J Mol Cell Biol
January 2025
Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
Insulin secretion is mainly regulated by two electrophysiological events, depolarization initiated by the closure of ATP-sensitive K+ (KATP) channels and repolarization mediated by K+ efflux. Quinine, a natural component commonly used for the treatment of malaria, has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting KATP channels. In this study, we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets.
View Article and Find Full Text PDFPurinergic inhibitory regulation of esophageal smooth muscle is mediated by P2Y receptors and ATP-dependent potassium channels in rats.
J Physiol Sci
January 2025
Department of Basic Veterinary Science, Laboratory of Physiology, Joint Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, 501-1193, Gifu, Japan; Department of Basic Veterinary Science, Laboratory of Physiology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, 501-1193, Gifu, Japan; Division of Animal Medical Science, Center for One Medicine Innovative Translational Research (COMIT), Gifu University Institute for Advanced Study, 1-1 Yanagido, 501-1193, Gifu, Japan.
Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!