ATP-sensitive potassium channels (KATP) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of KATP, we elucidated the structure of a hetero-octameric pancreatic KATP channel in complex with...

KATP blockers derived from cyanoguanidine KATP opener (P1075) chemistry were characterized in isolated rabbit mesenteric artery and evaluated functionally by their ability to antagonize maximal relaxation induced by pinacidil (1 microM) of norepinephrine (5 microM) contraction. PNU-89692, PNU-97025E and PNU-99963 were identified as KATP blockers with IC50 values of 860, 83 and 18 nM, respective...

The ATP-sensitive K+ channels (KATP) are characterized by strong inhibition by intracellular ATP but their activity is also modulated by various intra- and extracellular factors with complicated and undefined mechanism. These factors include a low concentration of ADP (or ATP/ADP ratio), a mildly low pH, G-protein coupled process, adenosine and so on. Intracellular ATP has a ligand action to in...

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent s...

Nitric oxide (NO) is known to be a potent messenger in the intracellular signal transduction system in many tissues. In pancreatic beta cells, NO has been reported to be formed from L-arginine through NO synthase. To elucidate the effect of NO on insulin secretion and to investigate the intracellular mechanism of its effect, we have used sodium nitroprusside (SNP) as a NO donor. SNP inhibited g...

Mice with genetic inhibition (AC3-I) of the multifunctional Ca(2+)/calmodulin dependent protein kinase II (CaMKII) have improved cardiomyocyte survival after ischemia. Some K(+) currents are up-regulated in AC3-I hearts, but it is unknown if CaMKII inhibition increases the ATP sensitive K(+) current (I(KATP)) that underlies ischemic preconditioning (IP) and confers resistance to ischemia. We hy...

ATP-sensitive K channels (KATP channels) play an important role in glucose homeostasis. A single nucleotide polymorphism (SNP) in the Kir6.2 subunit causes a point mutation of Glu23 to lysine and reduces the ATP sensitivity of pancreatic KATP channels. The SNP found in 58% of Caucasians accounts for 15% of type 2 diabetes. Here we show evidence for dysregulations of muscular KATP channels with ...

Effects of ER-001533 (ER), a newly synthesized vasorelaxant, on the membrane currents were examined in single ventricular cells of guinea pigs. The patch-clamp technique was used in the "whole-cell" and "inside-out" patch configurations. In the whole-cell clamp condition, ER induced a time-independent K'-dominant current, which was inhibited by glibenclamide (1-3 ,uM), suggesting that ER activa...

BACKGROUND We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (KATP) channels. However, the signal transduction involved in the KATP-channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)-sensitive G proteins may be involved in the si...

Adenosine triphosphate (ATP)–sensitive potassium (KATP) channels allow coupling of membrane potential to cellular metabolic status. Two KATP channel subtypes coexist in the myocardium, with one subtype located in the sarcolemma (sarcKATP) membrane and the other in the inner membrane of the mitochondria (mitoKATP). The KATP channels can be pharmacologically modulated by a family of structurally ...