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1.
Potent and selective activation of the pancreatic beta-cell type KATP channel by two novel diazoxide analogues 总被引:1,自引:0,他引:1
Aims/hypothesis We investigated the pharmacological properties of two novel ATP sensitive potassium (KATP) channel openers, 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) and 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414), on the cloned cardiac (Kir6.2/SUR2A), smooth muscle (Kir6.2/SUR2B) and pancreatic beta cell (Kir6.2/SUR1) types of KATP channel.Methods We studied the effects of these compounds on whole-cell currents through cloned KATP channels expressed in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes.Results In HEK 293 cells, NNC 55-0118 and NN414 activated Kir6.2/SUR1 currents with EC50 values of 0.33 µmol/l and 0.45 µmol/l, respectively, compared with that of 31 µmol/l for diazoxide. Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes, nor did they activate Kir6.2 expressed in the absence of SUR. Current activation was dependent on the presence of intracellular MgATP, but was not supported by MgADP.Conclusion/interpretation Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of KATP channel with a higher potency than diazoxide, by interaction with the SUR1 subunit. The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial.Abbreviations KATP channel ATP-sensitive potassium channel - SUR sulphonylurea receptor - KCO K+ channel opener - Kir inwardly rectifying K+ channel - TEVC two electrode voltage clamp - HEK293 cell Human Embryonic Kidney 293 cell 相似文献
2.
SUR, ABC proteins targeted by KATP channel openers 总被引:6,自引:0,他引:6
Moreau C Prost AL Dérand R Vivaudou M 《Journal of molecular and cellular cardiology》2005,38(6):951-963
The sulfonylurea receptor SUR is an ATP binding cassette (ABC) protein of the ABCC/MRP family. Unlike other ABC proteins, it has no intrinsic transport function, neither active nor passive, but associates with the potassium channel proteins Kir6.1 or Kir6.2 to form the ATP-sensitive potassium (K(ATP)) channel. Within the channel complex SUR serves as a regulatory subunit which fine-tunes the gating of Kir6.x in response to alterations in cellular metabolism. It constitutes a major pharmaceutical target as it binds numerous drugs, K(ATP) channel openers and blockers, capable of up- or down-regulating channel activity. We here review current knowledge on the molecular basis of the interaction of classical K(ATP) channel openers (cromakalim, pinacidil, diazoxide) with SUR. 相似文献
3.
Chao C Liang T Kang Y Lin X Xie H Feng ZP Gaisano HY 《Journal of molecular and cellular cardiology》2011,51(5):790-802
We previously demonstrated that syntaxin (Syn)-1A is present in the sarcolemma of rat cardiomyocytes and binds sulfonylurea receptor (SUR) 2A nucleotide binding folds (NBFs) to inhibit ATP-sensitive potassium (KATP) channel. Here, we examined for the precise domains within the NBFs of SUR2A that may interact with Syn-1A. Specifically, we tested truncated NBF protein segments encompassing the conserved motifs Walker A (WA), signature/Linker (L), and Walker B (WB). In vitro binding results indicate that the domains encompassing WA and L of NBF-1 and all three conserved motifs of NBF-2 bound Syn-1A. Electrophysiological studies, employing inside-out patch-clamp recordings from SUR2A/Kir6.2 expressing HEK cells and mouse cardiomyocytes, show that WB and L of NBF-1 and all three NBF-2 truncated protein segments reduced Syn-1A inhibition of SUR2A/KATP channels. Remarkably, these same NBF-1 and -2 truncated proteins could independently disrupt the intimate FRET interactions of full length SUR2A (− mCherry) and Syn-1A (− EGFP). These results taken together indicate that Syn-1A possibly maintains inhibition of cardiac ventricular KATP channels by binding to large regions of NBF-1 and NBF-2 to stabilize the NBF-1-NBF-2 heterodimer formation and prevent ATP-binding and ATP hydrolysis. Since KATP channels are closely coupled to metabolic states, we postulate that these very intimate Syn-1A-SUR2A interactions are critically important for myocardial protection during stress, in which profound changes in metabolic factors (pH, ATP) could modulate these Syn-1A-SUR2A interactions. 相似文献
4.
ATP-sensitive K+ channels of vascular smooth muscle cells 总被引:8,自引:0,他引:8
ATP-sensitive potassium channels (K(ATP)) of vascular smooth muscle cells represent potential therapeutic targets for control of abnormal vascular contractility. The biophysical properties, regulation and pharmacology of these channels have received intense scrutiny during the past twenty years, however, the molecular basis of vascular K(ATP) channels remains ill-defined. This review summarizes the recent advancements made in our understanding of the molecular composition of vascular K(ATP) channels with a focus on the evidence that hetero-octameric complexes of Kir6.1 and SUR2B subunits constitute the vascular K(ATP) subtype responsible for control of arterial diameter by vasoactive agonists. 相似文献
5.
Fedorov VV Glukhov AV Ambrosi CM Kostecki G Chang R Janks D Schuessler RB Moazami N Nichols CG Efimov IR 《Journal of molecular and cellular cardiology》2011,51(2):215-225
This study compared the effects of ATP-regulated potassium channel (KATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n = 11) or left (n = 2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n = 8) and non-failing human hearts without (NF, n = 3) or with (INF, n = 2) infarction. We also analyzed the mRNA expression of the KATP targets Kir6.1, Kir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n = 8) and CHF (n = 4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by − 21 ± 3% and − 27 ± 13%, p < 0.01) and ventricles (by − 28 ± 7% and − 28 ± 4%, p < 0.01). Diazoxide did not change APD (0 ± 5%) in NF atria. Pinacidil significantly decreased APDs in both atria (− 46 to −80%, p < 0.01) and ventricles (− 65 to − 93%, p < 0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p < 0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4 ± 6.1 Hz and 17.5 ± 5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts. 相似文献
6.
Chao CC Mihic A Tsushima RG Gaisano HY 《Journal of molecular and cellular cardiology》2011,50(3):401-407
Coordinated cardiac ion channel gating is fundamental for generation of action potential and excitability throughout the myocardium. The interaction of pore-forming ion channels with auxiliary subunits can regulate surface expression, localization and anchoring of these channels to plasma membrane. SNARE (soluble N-ethylmaleimide sensitive factors attachment protein or SNAP receptor) proteins mediate the targeting, docking, and fusion of intracellular vesicles for exocytotic release of neurotransmitters and hormones. In secretory neurons and neuroendocrine cells, some voltage-gated channels are physically coupled with SNARE proteins, resulting in alterations in channel gating and trafficking. Coupling of SNARE proteins to membrane ion channels is however not unique to secretory cells. We have demonstrated the expression of SNARE proteins in rodent myocardial tissue, and more importantly, functional interaction of SNARE proteins with cardiac KATP and Kv (Kv1.2, Kv2.1, Kv4.2, Kv4.3, and Kv11.1) channels. SNARE proteins, therefore, have similar fundamental functions in ion channel trafficking and regulation per se, independent of secretion. We now review the body of work of SNARE protein regulation on membrane ion channels in the heart. 相似文献
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Kim DK Cho EB Moon MJ Park S Hwang JI Kah O Sower SA Vaudry H Seong JY 《General and comparative endocrinology》2011,170(1):68-78
Gonadotropin-releasing hormone (GnRH) and its G protein-coupled receptor, GnRHR, play a pivotal role in the control of reproduction in vertebrates. To date, many GnRH and GnRHR genes have been identified in a large variety of vertebrate species using conventional biochemical and molecular biological tools in combination with bioinformatic tools. Phylogenetic approaches, primarily based on amino acid sequence identity, make it possible to classify these multiple GnRHs and GnRHRs into several lineages. Four vertebrate GnRH lineages GnRH1, GnRH2, GnRH3, and GnRH4 (for lamprey) are well established. Four vertebrate GnRHR lineages have also been proposed—three for nonmammalian GnRHRs and mammalian GnRHR2 as well as one for mammalian GnRHR1. However, these phylogenetic analyses cannot fully explain the evolutionary origins of each lineage and the relationships among the lineages. Rapid and vast accumulation of genome sequence information for many vertebrate species, together with advances in bioinformatic tools, has allowed large-scale genome comparison to explore the origin and relationship of gene families of interest. The present review discusses the evolutionary mechanism of vertebrate GnRHs and GnRHRs based on extensive genome comparison. In this article, we focus only on vertebrate genomes because of the difficulty in comparing invertebrate and vertebrate genomes due to their marked divergence. 相似文献