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Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea receptor 1 (SUR1) inhibition has shown promising results in predominantly male TBI. A phase II trial is ongoing. We investigated whether SUR1 inhibition effects on contusional TBI differ by sex given that this may inform clinical trial design and/or interpretation. We studied the moderating effects of sex on post-injury brain tissue loss in 142 male and female ATP-binding cassette transporter subfamily C member 8 (Abcc8) wild-type, heterozygote, and knockout mice (12–15 weeks). Monkey fibroblast-like cells and mouse brain endothelium-derived cells were used for in vitro studies. Mice were injured with controlled cortical impact and euthanized 21 days post-injury to assess contusion, brain, and hemisphere volumes (vs. genotype- and sex-matched naïves). Abcc8 knockout mice had smaller contusion volumes (p = 0.012) and larger normalized contralateral (right) hemisphere volumes (nRHV; p = 0.03) after injury versus wild type. This was moderated by sex: Contusions were smaller (p = 0.020), nRHV was higher (p = 0.001), and there was less global atrophy (p = 0.003) in male, but not female, knockout versus wild-type mice after TBI. Less atrophy occurred in males for each copy of Abcc8 lost (p = 0.023–0.002, all outcomes). In vitro, sex-determining region Y (SRY) stimulated Abcc8 promoter activity and increased Abcc8 expression. Loss of Abcc8 strongly protected against post-traumatic cerebral atrophy in male, but not female, mice. This may partly be mediated by SRY on the Y-chromosome. Sex differences may have important implications for ongoing and future trials of SUR1 blockade.

Introduction: Syzygium cumini (L.) has been known to be used for diabetes treatment in traditional Indian and Chinese medicine. The present study focuses on the evaluation for glucose uptake and insulin release in vitro and characterization of phytoconstituents of the hydro-ethanolic extract of Syzygium cumini seed (SCE). Further, this report covers the molecular docking findings of the bioactive constituents on the sulfonylurea receptor 1 (SUR1). Methods: A glucose uptake assay of SCE was used to estimate the glucose uptake from the cell lysates and the cell culture supernatants using insulin as the reference standard. Insulin release activity of SCE from RIN-5F cells was estimated using enzyme-linked immunosorbent assay. The phytoconstituents were isolated by preparative HPLC and characterized by mass spectrometry, nuclear magnetic resonance (NMR) and infrared spectroscopy. The molecular docking of bioactive constituents was carried on repaglinide bound to the SUR1. Results: In the presence of SCE, the glucose uptake through L6 myoblast cells increased by 19.91% at 40 µg/mL in comparison with the vehicle control (P < 0.05). Moreover, SCE showed 2.8-fold enhancement of insulin release at 40 µg/mL as compared to the vehicle controls (P < 0.05). Gallic and ellagic acids were the key phytoconstituents isolated from SCE. Molecular docking studies revealed that both gallic acid and ellagic acid bind to the repaglinide binding pocket of SUR1. Conclusion: SCE increases the release of insulin and enhances glucose uptake in vitro, which may contribute to its in vivo anti-diabetic activity. The presence of ellagic acid and gallic acid in SCE may be the cause for enhanced insulin release observed with SCE following binding to SUR1.

Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the KATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic KATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on KATP channel involvement in migraine. KATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of KATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various KATP channel subtypes.

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.

Aims/hypothesis Congenital hyperinsulinism caused by mutations in the K-ATP-channel-encoding genes (KATPHI) is a potentially life-threatening disorder of the pancreatic beta cells. No optimal medical treatment is available for patients with diazoxide-unresponsive diffuse KATPHI. Therefore, we aimed to create a model of KATPHI using patient induced pluripotent stem cell (iPSC)-derived islets. Methods We derived iPSCs from a patient carrying a homozygous ABCC8(V187D) mutation, which inactivates the sulfonylurea receptor 1 (SUR1) subunit of the K-ATP-channel. CRISPR-Cas9 mutation-corrected iPSCs were used as controls. Both were differentiated to stem cell-derived islet-like clusters (SC-islets) and implanted into NOD-SCID gamma mice. Results SUR1-mutant and -corrected iPSC lines both differentiated towards the endocrine lineage, but SUR1-mutant stem cells generated 32% more beta-like cells (SC-beta cells) (64.6% vs 49.0%, p = 0.02) and 26% fewer alpha-like cells (16.1% vs 21.8% p = 0.01). SUR1-mutant SC-beta cells were 61% more proliferative (1.23% vs 0.76%, p = 0.006), and this phenotype could be induced in SUR1-corrected cells with pharmacological K-ATP-channel inactivation. The SUR1-mutant SC-islets secreted 3.2-fold more insulin in low glucose conditions (0.0174% vs 0.0054%/min, p = 0.0021) and did not respond to K-ATP-channel-acting drugs in vitro. Mice carrying grafts of SUR1-mutant SC-islets presented with 38% lower fasting blood glucose (4.8 vs 7.7 mmol/l, p = 0.009) and their grafts failed to efficiently shut down insulin secretion during induced hypoglycaemia. Explanted SUR1-mutant grafts displayed an increase in SC-beta cell proportion and SC-beta cell nucleomegaly, which was independent of proliferation. Conclusions/interpretation We have created a model recapitulating the known pathophysiology of KATPHI both in vitro and in vivo. We have also identified a novel role for K-ATP-channel activity during human islet development. This model will enable further studies for the improved understanding and clinical management of KATPHI without the need for primary patient tissue.

In this work the anion-binding properties of three aromatic sulfonylurea derivatives in acetonitrile and dimethyl sulfoxide were explored by means of NMR titrations. It was found that the studied receptors effectively bind anions of low basicity (Cl−, Br−, I−, NO3− and HSO4−). The stoichiometry of the complexes with receptors containing one binding site was 1 : 1 exclusively, whereas in the case of the receptor containing two sulfonylurea groups 1 : 2 (receptor : anion) complexes were also detected in some cases. The presence of strongly basic anions (acetate and dihydrogen phosphate) led to the deprotonation of the sulfonylurea moiety. This completely hindered its anion-binding properties in DMSO and only proton transfer occurred upon the addition of basic anions to the studied receptors. In MeCN, a complex system of equilibria including both ligand deprotonation and anion binding was established. Since ionisation of receptors was proven to be a decisive factor defining the behaviour of the sulfonylurea receptors, their pKa values were determined using several deprotonation agents in both solvents. The results were interpreted in the context of receptor structures and solvent properties and applied for the identification of the interactions with basic anions.

Potassium channels are widely expressed in most types of cells in living organisms and regulate the functions of a variety of organs, including kidneys, neurons, cardiovascular organs, and pancreas among others. However, the functional roles of potassium channels in the reproductive system is less understood. This mini-review provides information about the localization and functions of potassium channels in the female reproductive system. Five types of potassium channels, which include inward-rectifying (Kir), voltage-gated (Kv), calcium-activated (KCa), 2-pore domain (K2P), and rapidly-gating sodium-activated (Slo) potassium channels are expressed in the hypothalamus, ovaries, and uterus. Their functions include the regulation of hormone release and feedback by Kir6.1 and Kir6.2, which are expressed in the luteal granulosa cells and gonadotropin-releasing hormone neurons respectively, and regulate the functioning of the hypothalamus-pituitary-ovarian axis and the production of progesterone. Both channels are regulated by subtypes of the sulfonylurea receptor (SUR), Kir6.1/SUR2B and Kir6.2/SUR1. Kv and Slo2.1 affect the transition from uterine quiescence in late pregnancy to the state of strong myometrial contractions in labor. Intermediate- and small-conductance KCa modulate the vasodilatation of the placental chorionic plate resistance arteries via the secretion of nitric oxide and endothelium-derived hyperpolarizing factors. Treatment with specific channel activators and inhibitors provides information relevant for clinical use that could help alter the functions of the female reproductive system.

The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion. This study investigates how different key points of the stimulus-secretion coupling in mouse islets and β-cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca2+]c in islets at a concentration of 100 µM along with a stimulating glucose concentration. DXO and DXM increased insulin secretion approximately 30-fold at a substimulatory glucose concentration (3 mM). Patch-clamp experiments revealed that 100 µM DXM directly inhibited KATP channels by about 70%. Of note, DXM decreased the current through L-type Ca2+ channels about 25%, leading to a transient reduction in Ca2+ action potentials. This interaction might explain why elevating DXM to 500 µM drastically decreased insulin release. DXO inhibited KATP channels almost equally. In islets of KATP channel-deficient sulfonylurea receptor 1 knockout mice, the elevating effects of 100 µM DXM on [Ca2+]c and insulin release were completely lost. By contrast, 100 µM DXO still increased glucose-stimulated insulin release around 60%. In summary, DXM-induced alterations in stimulus-secretion coupling of wild-type islets result from a direct block of KATP channels and are partly counteracted by inhibition of L-type Ca2+ channels. The stimulatory effect of DXO seems to be based on a combined antagonism on KATP channels and NMDA receptors and already occurs under resting conditions. Consequently, both compounds seem not to be suitable candidates for treatment of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the use of dextromethorphan as an antidiabetic drug can cause unpredictable alterations in insulin secretion by direct interaction with KATP and L-type Ca2+ channels besides its actual target, the NMDA receptor.

Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of ATP-sensitive potassium channels (KATP channels) and the receptor of antidiabetic drugs, such as glibenclamide, which induce insulin secretion in pancreatic β cells. However, the expression and role of SUR1 in cancer are unknown. In this study, we found that SUR1 expression was elevated in human non–small cell lung carcinoma (NSCLC) tissues and cell lines. SUR1 silencing suppressed the growth of NSCLC cells, while SUR1 overexpression promoted cell growth. Targeting SUR1 with glibenclamide suppressed cell growth, cell-cycle progression, epithelial–mesenchymal transition (EMT), and cell migration. Moreover, SUR1 directly interacted with p70S6K and upregulated p70S6K phosphorylation and activity. In addition, glibenclamide inhibited p70S6K, and overexpression of p70S6K partially reversed the growth-inhibiting effect of glibenclamide. Furthermore, glibenclamide upregulated the expression of the tumor suppressor Krüppel-like factor 4 (KLF4), and silencing KLF4 partially reversed the inhibitory effect of glibenclamide on cell growth, EMT, and migration. We found that SUR1 targeted p70S6K to downregulate KLF4 expression by enhancing DNA-methyltransferase 1–mediated methylation of the KLF4 promoter. Finally, in xenograft mouse models, SUR1 expression silencing or glibenclamide treatment inhibited the growth of A549 tumors, downregulated p70S6K activity, and upregulated KLF4 expression. These findings suggested that SUR1 expression was elevated in some NSCLC tissues and functioned as a tumor enhancer. Targeting SUR1 with glibenclamide inhibited NSCLC through downregulation of p70S6K activity and subsequent upregulation of the expression of the tumor suppressor gene KLF4. SUR1 can be developed as a new target for cancer therapy and glibenclamide has potential anticancer effects.

K(ATP) channels are metabolic sensors that translate intracellular ATP/ADP balance into membrane excitability. The molecular composition of K(ATP) includes an inward-rectifier potassium channel (Kir) and an ABC transporter–like sulfonylurea receptor (SUR). Although structures of K(ATP) have been determined in many conformations, in all cases, the pore in Kir is closed. Here, we describe human pancreatic K(ATP) (hK(ATP)) structures with an open pore at 3.1- to 4.0-Å resolution using single-particle cryo-electron microscopy (cryo-EM). Pore opening is associated with coordinated structural changes within the ATP-binding site and the channel gate in Kir. Conformational changes in SUR are also observed, resulting in an area reduction of contact surfaces between SUR and Kir. We also observe that pancreatic hK(ATP) exhibits the unique (among inward-rectifier channels) property of PIP(2)-independent opening, which appears to be correlated with a docked cytoplasmic domain in the absence of PIP(2).

ATP-sensitive K+ (KATP) channels couple cellular metabolism to electrical activity in many cell types. Wild-type KATP channels are comprised of four pore forming (Kir6.x) and four regulatory (sulfonylurea receptor, SURx) subunits that each contain RKR endoplasmic reticulum retention sequences that serve to properly translocate the channel to the plasma membrane. Truncated Kir6.x variants lacking RKR sequences facilitate plasma membrane expression of functional Kir6.x in the absence of SURx; however, the effects of channel truncation on plasma membrane orientation have not been explored. To investigate the role of truncation on plasma membrane orientation of ATP sensitive K+ channels, three truncated variants of Kir6.2 were used (Kir6.2ΔC26, 6xHis-Kir6.2ΔC26, and 6xHis-EGFP-Kir6.2ΔC26). Oocyte expression of Kir6.2ΔC26 shows the presence of a population of inverted inserted channels in the plasma membrane, which is not present when co-expressed with SUR1. Immunocytochemical staining of intact and permeabilized HEK293 cells revealed that the N-terminus of 6xHis-Kir6.2ΔC26 was accessible on both sides of the plasma membrane at roughly equivalent ratios, whereas the N-terminus of 6xHis-EGFP-Kir6.2Δ26 was only accessible on the intracellular face. In HEK293 cells, whole-cell electrophysiological recordings showed a ca. 50% reduction in K+ current upon addition of ATP to the extracellular solution for 6xHis-Kir6.2ΔC26, though sensitivity to extracellular ATP was not observed in 6xHis-EGFP-Kir6.2ΔC26. Importantly, the population of channels that is inverted exhibited similar function to properly inserted channels within the plasma membrane. Taken together, these data suggest that in the absence of SURx, inverted channels can be formed from truncated Kir6.x subunits that are functionally active which may provide a new model for testing pharmacological modulators of Kir6.x, but also indicates the need for added caution when using truncated Kir6.2 mutants.

Hinchazón celular; Edema; Traumatismo cerebral Cellular swelling; Edema; Traumatic brain injury Inflor cel·lular; Edema; Traumatisme cerebral Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials. No funding directly supported the writing of this review. R.M.J. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS101036; R01NS115815), and the Barrow Neurological Foundation. J.M.S. is supported by grants from the Department of Veterans Affairs (I01RX003060; 1I01BX004652), the Department of Defense (SC170199), the National Heart, Lung and Blood Institute (R01HL082517) and the NINDS (R01NS102589; R01NS105633).

Sulfonylurea receptor (SUR) belongs to the adenosine 5′-triphosphate (ATP)-binding cassette (ABC) transporter family; however, SUR is associated with ion channels and acts as a regulatory subunit determining the opening or closing of the pore. Abcc8 and Abcc9 genes code for the proteins SUR1 and SUR2, respectively. The SUR1 transcript encodes a protein of 1582 amino acids with a mass around 140–177 kDa expressed in the pancreas, brain, heart, and other tissues. It is well known that SUR1 assembles with Kir6.2 and TRPM4 to establish KATP channels and non-selective cation channels, respectively. Abbc8 and 9 are alternatively spliced, and the resulting transcripts encode different isoforms of SUR1 and SUR2, which have been detected by different experimental strategies. Interestingly, the use of binding assays to sulfonylureas and Western blotting has allowed the detection of shorter forms of SUR (~65 kDa). Identity of the SUR1 variants has not been clarified, and some authors have suggested that the shorter forms are unspecific. However, immunoprecipitation assays have shown that SUR2 short forms are part of a functional channel even coexisting with the typical forms of the receptor in the heart. This evidence confirms that the structure of the short forms of the SURs is fully functional and does not lose the ability to interact with the channels. Since structural changes in short forms of SUR modify its affinity to ATP, regulation of its expression might represent an advantage in pathologies where ATP concentrations decrease and a therapeutic target to induce neuroprotection. Remarkably, the expression of SUR1 variants might be induced by conditions associated to the decrease of energetic substrates in the brain (e.g. during stroke and epilepsy). In this review, we want to contribute to the knowledge of SUR1 complexity by analyzing evidence that shows the existence of short SUR1 variants and its possible implications in brain function.