katp channel

Vascular smooth muscle KATP channels critically regulate blood flow and blood pressure by modulating vascular tone, and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular KATP ) over Kir6.2/SUR1 (pancreatic KATP ) has alluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6...

Stimulation of the calcium-sensing receptor (CaSR) induces both vasoconstrictions and vasorelaxations but underlying cellular processes remain unclear. This study investigates expression and effect of stimulating the CaSR by increasing external Ca2+ concentration ([Ca2+ ]o ) on contractility of rat mesenteric arteries. Immunofluorescence studies showed expression of the CaSR in perivascular nerves, vascular smooth muscle cells (VSMCs), and vascular endothelium cells. Using wire myography, increasing [Ca2+ ]o from 1 to 10 mM induced vasorelaxations which were inhibited by the calcilytic Calhex-231 and partially dependent on a functional endothelium...

Migraine, a common neurological disorder, impacts over a billion individuals globally. Its complex aetiology involves various signalling cascades. Hypoxia causes headaches such as high-altitude headache and acute mountain sickness which share phenotypical similarities with migraine. Epidemiological data indicate an increased prevalence of migraine with and without aura in high-altitude populations. Experimental studies have further shown that hypoxia can induce migraine attacks. This review summarizes evidence linking hypoxia to migraine, delves into potential pathophysiological mechanisms and highlights research gaps...

CONTEXT: Low dose sulphonylureas have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE: To evaluate potential synergy between low dose sulphonylurea plus DPP4 inhibitor. DESIGN: Unblinded randomised crossover study. SETTING: Clinical Research Centre, University of Dundee. PARTICIPANTS: 30 participants with T2DM (HbA1c < 64 mmol/mol) treated with diet or metformin...

Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known that glucose stimulates insulin secretion from pancreatic β-cells, mainly via the KATP depolarization channel, but whether other nutrients directly regulate the repolarization K+ channel to promote insulin secretion is unknown...

AIM: Despite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet β-cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into β-cells and its acute and chronic intracellular interactions. METHODS: The molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 β-cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2-20 mM), using the hormone release and imaging of intracellular signals as surrogate read-outs...

SUR2, similar to SUR1, is a regulatory subunit of the ATP-sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand-dependent dynamic conformational changes, transitioning between an inhibitory inward-facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1...

Congenital hyperinsulinism (CHI; OMIM: 256450) is characterized by persistent insulin secretion despite severe hypoglycemia. The most common causes are variants in the ATP-binding cassette subfamily C member 8(ABCC8) and potassium inwardly-rectifying channel subfamily J member 11(KCNJ11) genes. These encode ATP-sensitive potassium (KATP ) channel subunit sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) proteins. A 7-day-old male infant presented with frequent hypoglycemic episodes and was clinically diagnosed with CHI, underwent trio-whole-exome sequencing, revealing compound heterozygous ABCC8 variants (c...

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harboring different homozygous LoF variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels...

BACKGROUND: Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied. OBJECTIVE: The study aimed to characterize the effect of POH on human umbilical arteries (HUA). METHODS: Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated...

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0...

Previous studies have suggested that L-cysteine regulates gut motility through hydrogen sulfide. However, the mechanisms involved in the L-cysteine-induced response have not been extensively studied. This study aimed to investigate the underlying mechanisms of action of L-cysteine on spontaneous contraction of rat colon. Longitudinal and circular muscle strips from rat middle colon were prepared to measure the spontaneous contractile activities of colon in an organ bath system. Whole-cell voltage-clamp techniques were applied to record the currents of L-type voltage-dependent Ca2+ channels (VDCCs) and voltage-gated K+ channels (Kv) in isolated smooth muscle cells (SMCs) from colon...

Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of releasing hydrogen sulfide (H2 S), an endogenous pleiotropic gasotransmitter responsible for anti-ischemic cardioprotective effects also through the involvement of mitoK channels. Erucin (ERU) is a natural isothiocyanate resulting from the enzymatic hydrolysis of glucosinolates (GSLs) present in Eruca sativa Mill. seeds, an edible plant of the Brassicaceae family...

Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (KATP ) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of KATP channel opener (nicorandil) as well as α and β adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice...

Activation of adenosine triphosphate-sensitive potassium (KATP) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches...

Studies have examined the therapeutic effect of levosimendan on cardiovascular diseases such as heart failure, perioperative cardiac surgery, and septic shock, but the specific mechanism in mice remains largely unknown. This study aimed to investigate the relaxation mechanism of levosimendan in the thoracic aorta smooth muscle of mice. Levosimendan-induced relaxation of isolated thoracic aortic rings that were precontracted with norepinephrine (NE) or KCl was recorded in an endothelium-independent manner. Vasodilatation by levosimendan was not associated with the production of the endothelial relaxation factors NO and PGI2...

ATP-sensitive potassium channels (KATP) are inhibited by ATP but activated by Mg-ADP, coupling the intracellular ATP/ADP ratio to the potassium conductance of the plasma membrane. Although there has been progress in determining the structure of KATP, the functional significance of the domain-domain interface in the gating properties of KATP channels remains incompletely understood. In this study, we define the structure of KATP as two modules: KATPcore and SURABC . Based on this model, we identified two functionally important interfaces between these two modules, namely interface I and interface II...

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP ) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice...

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries...

OBJECTIVE: Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (KATP ) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the KATP channel inhibitor glibenclamide would attenuate triggered headache in healthy volunteers have proven unsuccessful. It is questionable, however, whether target engagement was achieved in these clinical studies. METHODS: Literature data for human glibenclamide pharmacokinetics, plasma protein binding and functional IC50 values were used to predict the KATP receptor occupancy (RO) levels obtained after glibenclamide dosing in the published exploratory clinical headache provocation studies...