Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic beta-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.
Adenosine Triphosphate ; Glucose ; Homeostasis ; Insulin ; KATP Channels ; Polyphosphates ; Potassium

In order to clarify the cause of intracellular ATP dependency on Zn2+ blockade of KATP channels in pancreatic beta cells, we investigated the KATP channel activity during external Zn2+ application using voltage clamp technique. Cultured beta cells were used for patch-clamp experiment. When 3 mM glucose was applied in bath, KATP channel activity was increased transiently by externally applied Zn2+ in the cell-attached mode and was recoverable. The KATP channel activity was, however, consistently increased by Zn2+ application during the 0 mM glucose in bath. Inside-out mode, internally applied Zn2+ elicited no response on the KATP channels. Another divalent cation, Mn2+, didn't have any effect on the KATP channels. Therefore, This effect, so-called external glucose-dependency on Zn2+ blockade of the KATP channels, might be due to intracellular Zn2+ metabolism which induces ATP consumption. This appears to be a mechanism that the Zn2+ blockade of the KATP channels in the pancreatic beta cells depends on the intracellular ATP concentration.
Adenosine Triphosphate* ; Baths ; Glucose ; Insulin-Secreting Cells* ; KATP Channels* ; Metabolism

Animals ; Arrhythmias, Cardiac ; Humans ; KATP Channels ; Mitochondria ; Myocardial Ischemia

Ischemic damage is one of the most serious problems. The openers of KATP channel have been suggested to have an effect to limit the ischemic damage. However, it is not yet clear how KATP channels of a cell correspond to hypoxic damage. To address the question, N2a cells were exposed to two different hypoxic conditions as follows: 6 hours hypoxia followed by 3 hours reperfusion and 12 hours hypoxia followed by 3 hours reperfusion. As the results, 6 hours hypoxic treatment increased glibenclamide-sensitive basal KATP current activity (approximately 6.5-fold at 0 mV test potential) when compared with nomoxic condition. In contrast, 12 hours hypoxic treatment induced a relatively smaller change in the KATP current density (2.5-fold at 0 mV test potential). Additionally, in experiments where KATP channels were opened using diazoxide, the hypoxia for 6 hours significantly increased the current density in comparison to control condition (p < 0.001). Interestingly, the augmentation in the KATP current density reduced after exposure to the 12 hours hypoxic condition (p < 0.001). Taken together, these results suggest that KATP channels appear to be recruited more in cells exposed to the 6 hours hypoxic condition and they may play a protective role against hypoxia-reperfusion damage within the time range.
Animals ; Anoxia ; Diazoxide ; Glyburide ; KATP Channels ; Mice* ; Neuroblastoma* ; Potassium Channels* ; Potassium* ; Reperfusion

OBJECTIVE: The purpose of this study was to investigate the effects of haloperidol on [Ca2+]i in hamster insulinoma cells (HIT T-15). METHODS: [Ca2+]i levels were measured by calcium imaging techniques, and membrane potential ionic currents were recorded using conventional patch-clamp methods. RESULTS: Haloperidol induced a transient [Ca2+]i increase, which was abolished by the removal of extracellular Ca2+ or pretreatment with Ca2+ channel blockers (nimodipine and mibefradil). Haloperidol depolarized the membrane potential and inhibited the ATP-sensitive K+ (KATP) channels. Sigma receptor agonists, (+)-SKF10047 and ifenprodil, induced a transient [Ca2+]i increase similar to haloperidol. BD1047, a sigma receptor antagonist, completely blocked the [Ca2+]i increase induced by haloperidol. Haloperidol inhibited the KCl-induced [Ca2+]i increase and voltage-dependent Ca2+ currents. Sigma receptor agonists [(+)-SKF10047, ifenprodil] also inhibited the KCl-induced [Ca2+]i increase. CONCLUSION: Our results suggest that haloperidol induces depolarization, which increases [Ca2+]i by voltage-gated Ca2+ currents via the closing of KATP channels. Haloperidol also inhibits KCl-induced [Ca2+]i increases in the same manner. These effects of haloperidol seemed to be mediated by sigma receptors, which might be linked to the pathogenesis of haloperidol-induced diabetes mellitus.
Animals ; Calcium ; Cricetinae ; Diabetes Mellitus ; Haloperidol* ; Insulinoma* ; KATP Channels ; Membrane Potentials ; Receptors, sigma

BACKGROUND: It has been generally accepted that Cisapride (Prepulsid?or propulsid?), a widely used gastrointestinal prokinetic agent, is associated with Torsades de Points, a life-threatening arrhythmia. Recently, cisapride-induced APD (action potential duration)-prolongation was inhibited by glibenclamide, a KATP channel blocker. But the direct effect of cisapride on K(ATP) channels has not been studied until now. Therefore, we investigated cisapride's effects on KATP channels of isolated rat ventricular myocytes. METHODS: After the isolation of rat ventricular myocytes, we analysed the single channel current with patch pipettes. The method of analysis was the student t-test. RESULTS: 1) Cisapride (10(-6) M- 10(-4) M) inhibited KATP channel opening without changing channel conductance Ki was about 20micronM, and Hill coefficient was 0.75. 2) Cisapride inhibited pinacidil-induced KATP channel opening in the cell attached mode. CONCLUSIONS: These results suggest that cisapride-induced APD prolongation and arrythmic effects may be partly related to KATP channel inhibition.
Animals ; Arrhythmias, Cardiac ; Cisapride* ; Glyburide ; Humans ; KATP Channels ; Muscle Cells ; Rats

ATP-sensitive potassium channels (K), as an inward rectifying potassium channel, are widely distributed in many types of tissues. Kare activated by the depletion of ATP level and the increase in oxidative stress in cells. The activity of Kcouples cell metabolism with electrical activity and results in membrane hyperpolarization. Kare ubiquitously distributed in the brain, including substantia nigra, hippocampus, hypothalamus, cerebral cortex, dorsal nucleus of vagus and glial cells, and participate in neuronal excitability, mitochondria homeostasis and neurotransmitter release. Accumulating lines of evidence suggest that Kare the major contributing factors in the pathogenesis of Parkinson's disease (PD). This review discussed the association of Kwith the pathogenic processes of PD by focusing on the roles of Kon the degeneration of dopaminergic neurons, the functions of mitochondria, the firing pattern of dopaminergic neurons in the substantia nigra, the α-synuclein secretion from striatum, and the microglia activation.
Dopaminergic Neurons ; Humans ; KATP Channels ; Mitochondria ; Oxidative Stress ; Parkinson Disease ; Synaptic Transmission

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.
Humans ; KATP Channels ; drug effects ; physiology ; Mitochondria ; metabolism ; Parkinson Disease ; metabolism ; therapy

Background: Recent in vivo experimental evidence suggests that isoflurane-induced cardioprotection may involve KATP channel activation. However, it was demonstrated that isofluran inhibited KATP channel activities in the inside-out patch mode. To explain this discrepancy, the present investigation tested the hypothesis that a metabolite of isoflurane, trifluoroacetic acid (TFA), contributes to isoflurnae-induced cardioprotection via KATP channel activation during myocardial ischemia and reperfusion. Methods: Single ventricular myocytes were isolated from rabbit hearts by an enzymatic dissociation procedure. Patch-clamp techniques were used to record single-channel currents. KATP channel activities were assessed before and after the application of TFA with the inside-out patch mode. Results: TFA enhanced channel activity in a concentration-dependent fashion. The concentration of TFA for half-maximal activation and the Hill coefficient were 0.03 mM and 1.2, respectively. TFA did not affect the single channel conductance of KATP channels. Analysis of open and closed time distributions showed that TFA increased burst duration and decreased the interburst interval without changes in open and closed time distributions shorter than 5 ms. TFA diminished ATP sensitivity of KATP channels in a concentration-response relationship for ATP. Conclusions: TFA, a metabolite of isoflurane, enhanced KATP channel activity in a concentration-dependent fashion. These results imply that TFA could mediate isoflurane-induced cardioprotection via KATP channel activation during myocardial ischemia and reperfusion.
Adenosine Triphosphate ; Heart ; Isoflurane* ; KATP Channels* ; Muscle Cells* ; Myocardial Ischemia ; Patch-Clamp Techniques ; Reperfusion ; Trifluoroacetic Acid

ATP-sensitive potassium channels (KATP channels) play an important role in insulin secretion from pancreatic beta cells. We have investigated the effect of propofol on KATP channels in cultured single pancreatic beta cells of rats. Channel activity was recorded from membrane patches using the patch-clamp technique. In the inside-out configuration bath-applied propofol inhibited the KATP channel activities in a dose-dependent manner. The half-maximal inhibition dose (ED50) was 48.6+/-8.4 micrometer and the Hill coefficient was 0.73 0.11. Single channel conductance calculated from the slope of the relationship between single channel current and pipette potential (+20~+100 mV) was not significantly altered by propofol (control: 60.0+/-2.7 pS, 0.1 mM propofol: 58.7+/-3.5 pS). However, mean closed time was surely increased. Above results indicate that propofol blocks the KATP channels in the pancreatic beta cells in the range of its blood concentrations during anesthesia, suggesting a possible effect on insulin secretion and blood glucose level.
Anesthesia ; Animals ; Blood Glucose ; Insulin ; Insulin-Secreting Cells ; KATP Channels* ; Membranes ; Patch-Clamp Techniques ; Propofol* ; Rats*