Trafficking of ATP-sensitive potassium channels in health and disease

2007 ◽  
Vol 35 (5) ◽  
pp. 1055-1059 ◽  
Author(s):  
A. Sivaprasadarao ◽  
T.K. Taneja ◽  
J. Mankouri ◽  
A.J. Smith
Keyword(s):  
Insulin Secretion ◽  
Potassium Channels ◽  
Cell Surface ◽  
Genetic Diseases ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Severe Form ◽  
Coated Vesicle ◽  
Congenital Hyperinsulinism ◽  
Sulfonylurea Receptor

KATP channels (ATP-sensitive potassium channels), comprising four subunits each of Kir6.2 (inwardly rectifying potassium channel 6.2) and the SUR1 (sulfonylurea receptor 1), play a central role in glucose-stimulated insulin secretion by the pancreatic β-cell. Changes in the number of channels at the cell surface are associated with genetic diseases of aberrant insulin secretion, including CHI (congenital hyperinsulinism) and NDM (neonatal diabetes mellitus). The present review summarizes advances in our understanding of the vesicular trafficking of normal KATP channels and how genetic mutations in Kir6.2 interfere with such trafficking. A mutation, E282K, causing CHI, was found to disrupt a DXE [di-acidic ER (endoplasmic reticulum)-exit signal], thereby preventing its assembly into COPII (coatamer protein II)-coated vesicles and subsequent ER exit. The resultant decrease in the cell-surface density of the channel could explain the disease phenotype. Two mutations, Y330C and F333I, reported in patients with NDM, disrupted an endocytic traffic signal, thereby impairing CCV (clathrin-coated vesicle) formation and endocytosis. The consequent increase in the density of KATP channels, together with an attenuated sensitivity to ATP reported previously, may account for the severe form of NDM.

scholarly journals A novel high-affinity inhibitor against the human ATP-sensitive Kir6.2 channel

2018 ◽  
Vol 150 (7) ◽  
pp. 969-976 ◽  
Author(s):  
Yajamana Ramu ◽  
Yanping Xu ◽  
Zhe Lu
Keyword(s):  
Insulin Secretion ◽  
Specific Inhibitor ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Sulfonylurea Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
High Affinity ◽  
New Strategy ◽  
Extracellular Side

The adenosine triphosphate (ATP)-sensitive (KATP) channels in pancreatic β cells couple the blood glucose level to insulin secretion. KATP channels in pancreatic β cells comprise the pore-forming Kir6.2 and the modulatory sulfonylurea receptor 1 (SUR1) subunits. Currently, there is no high-affinity and relatively specific inhibitor for the Kir6.2 pore. The importance of developing such inhibitors is twofold. First, in many cases, the lack of such an inhibitor precludes an unambiguous determination of the Kir6.2's role in certain physiological and pathological processes. This problem is exacerbated because Kir6.2 knockout mice do not yield the expected phenotypes of hyperinsulinemia and hypoglycemia, which in part, may reflect developmental adaptation. Second, mutations in Kir6.2 or SUR1 that increase the KATP current cause permanent neonatal diabetes mellitus (PNDM). Many patients who have PNDM have been successfully treated with sulphonylureas, a common class of antidiabetic drugs that bind to SUR1 and indirectly inhibit Kir6.2, thereby promoting insulin secretion. However, some PNDM-causing mutations render KATP channels insensitive to sulphonylureas. Conceptually, because these mutations are located intracellularly, an inhibitor blocking the Kir6.2 pore from the extracellular side might provide another approach to this problem. Here, by screening the venoms from >200 animals against human Kir6.2 coexpressed with SUR1, we discovered a small protein of 54 residues (SpTx-1) that inhibits the KATP channel from the extracellular side. It inhibits the channel with a dissociation constant value of 15 nM in a relatively specific manner and with an apparent one-to-one stoichiometry. SpTx-1 evidently inhibits the channel by primarily targeting Kir6.2 rather than SUR1; it inhibits not only wild-type Kir6.2 coexpressed with SUR1 but also a Kir6.2 mutant expressed without SUR1. Importantly, SpTx-1 suppresses both sulfonylurea-sensitive and -insensitive, PNDM-causing Kir6.2 mutants. Thus, it will be a valuable tool to investigate the channel's physiological and biophysical properties and to test a new strategy for treating sulfonylurea-resistant PNDM.

scholarly journals Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

2016 ◽  
Vol 149 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Maria S. Remedi ◽  
Jonathan B. Friedman ◽  
Colin G. Nichols
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Vascular System ◽  
Wild Type Mouse ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Gain Of Function ◽  
Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

ATP-sensitive and inwardly rectifying potassium channels in smooth muscle

1997 ◽  
Vol 77 (4) ◽  
pp. 1165-1232 ◽  
Author(s):  
J. M. Quayle ◽  
M. T. Nelson ◽  
N. B. Standen
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Protein Kinase ◽  
Potassium Channels ◽  
Membrane Conductance ◽  
Katp Channels ◽  
Muscle Membrane ◽  
Sulfonylurea Receptor ◽  
Kir Channels ◽  
Inwardly Rectifying

The properties and roles of ATP-sensitive (KATP) and inwardly rectifying (KIR) potassium channels are reviewed. Potassium channels regulate the membrane potential of smooth muscle, which controls calcium entry through voltage-dependent calcium channels, and thereby contractility through changes in intracellular calcium. The KATP channel is likely to be composed of members of the inward rectifier channel gene family (Kir6) and sulfonylurea receptor proteins. The KIR channels do not appear to be as widely distributed as KATP channels in smooth muscle and may provide a mechanism by which changes in extracellular K+ can alter smooth muscle membrane potential, and thereby arterial diameter. The KATP channels contribute to the resting membrane conductance of some types of smooth muscle and can open under situations of metabolic compromise. The KATP channels are targets of a wide variety of vasodilators and constrictors, which act, respectively, through adenosine 3',5'-cyclic monophosphate/protein kinase A and protein kinase C. The KATP channels are also activated by a number of synthetic vasodilators (e.g., diazoxide and pinacidil) and are inhibited by the oral hypoglycemic sulfonylurea drugs (e.g., glibenclamide). Together, KATP and KIR channels are important regulators of smooth muscle function and represent important therapeutic targets.

scholarly journals Mechanism of pharmacochaperoning in KATP channels revealed by cryo-EM

2019 ◽  
Author(s):  
Gregory M. Martin ◽  
Min Woo Sung ◽  
Zhongying Yang ◽  
Laura M. Innes ◽  
Balamurugan Kandasamy ◽  
...  
Keyword(s):  
Katp Channels ◽  
Binding Pocket ◽  
Surface Expression ◽  
Drug Binding ◽  
Cell Surface Expression ◽  
Common Mechanism ◽  
Congenital Hyperinsulinism ◽  
Sulfonylurea Receptor ◽  
N Terminus ◽  
Channel Expression

AbstractATP-sensitive potassium (KATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse KATPinhibitors have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of KATPchannels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within the SUR1 ABC core, allowing it to act as a firm “handle” for the assembly of metastable mutant SUR1-Kir6.2 complexes.

scholarly journals Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study

2014 ◽  
Vol 144 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Peter Proks ◽  
Heidi de Wet ◽  
Frances M. Ashcroft
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Mechanistic Study ◽  
Xenopus Laevis Oocytes ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Stimulatory Action ◽  
Channel Inhibition

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.

scholarly journals Mechanism of pharmacochaperoning in a mammalian KATP channel revealed by cryo-EM

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Gregory M Martin ◽  
Min Woo Sung ◽  
Zhongying Yang ◽  
Laura M Innes ◽  
Balamurugan Kandasamy ◽  
...  
Keyword(s):  
Katp Channel ◽  
Katp Channels ◽  
Binding Pocket ◽  
Surface Expression ◽  
Drug Binding ◽  
Cell Surface Expression ◽  
Common Mechanism ◽  
Congenital Hyperinsulinism ◽  
Sulfonylurea Receptor ◽  
N Terminus

ATP-sensitive potassium (KATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic β-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse KATP inhibitors are known to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of a mammalian KATP channel bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. We found all three drugs bind within a common pocket in SUR1. Further, we found the N-terminus of Kir6.2 inserted within the central cavity of the SUR1 ABC core, adjacent the drug binding pocket. The findings reveal a common mechanism by which diverse compounds stabilize the Kir6.2 N-terminus within SUR1’s ABC core, allowing it to act as a firm ‘handle’ for the assembly of metastable mutant SUR1-Kir6.2 complexes.

scholarly journals Neonatal Diabetes Caused by Mutations in Sulfonylurea Receptor 1: Interplay between Expression and Mg-Nucleotide Gating Defects of ATP-Sensitive Potassium Channels

2010 ◽  
Vol 31 (5) ◽  
pp. 779-779
Author(s):  
Qing Zhou ◽  
Intza Garin ◽  
Luis Castaño ◽  
Jesús Argente ◽  
Ma. Teresa Muñoz-Calvo ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Neonatal Diabetes ◽  
Sulfonylurea Receptor ◽  
Sulfonylurea Receptor 1

Molecular cell biology of KATP channels: implications for neonatal diabetes

2007 ◽  
Vol 9 (21) ◽  
pp. 1-17 ◽  
Author(s):  
Andrew J. Smith ◽  
Tarvinder K. Taneja ◽  
Jamel Mankouri ◽  
Asipu Sivaprasadarao
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Biosynthetic Pathway ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Electric Signal ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Molecular Cell Biology ◽  
Molecular Signals

AbstractATP-sensitive potassium (KATP) channels play a key role in the regulation of insulin secretion by coupling glucose metabolism to the electrical activity of pancreatic β-cells. To generate an electric signal of suitable magnitude, the plasma membrane of the β-cell must contain an appropriate number of channels. An inadequate number of channels can lead to congenital hyperinsulinism, whereas an excess of channels can result in the opposite condition, neonatal diabetes. KATP channels are made up of four subunits each of Kir6.2 and the sulphonylurea receptor (SUR1), encoded by the genes KCNJ11 and ABCC8, respectively. Following synthesis, the subunits must assemble into an octameric complex to be able to exit the endoplasmic reticulum and reach the plasma membrane. While this biosynthetic pathway ensures supply of channels to the cell surface, an opposite pathway, involving clathrin-mediated endocytosis, removes channels back into the cell. The balance between these two processes, perhaps in conjunction with endocytic recycling, would dictate the channel density at the cell membrane. In this review, we discuss the molecular signals that contribute to this balance, and how an imbalance could lead to a disease state such as neonatal diabetes.

scholarly journals Chronic Glucose Exposure Systematically Shifts the Oscillatory Threshold of Mouse Islets: Experimental Evidence for an Early Intrinsic Mechanism of Compensation for Hyperglycemia

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 611-623 ◽  
Author(s):  
Eric Glynn ◽  
Benjamin Thompson ◽  
Suryakiran Vadrevu ◽  
Shusheng Lu ◽  
Robert T. Kennedy ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Electrical Activity ◽  
Katp Channels ◽  
Sulfonylurea Receptor ◽  
Intrinsic Mechanism ◽  
Oscillation Modes ◽  
Mouse Islets ◽  
Glucose Sensitivity ◽  
Glucose Threshold

Abstract Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca2+ and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance. To test this experimentally, we exposed isolated mouse islets to varying glucose concentrations overnight and monitored their glucose sensitivity the next day by measuring intracellular Ca2+, electrical activity, and insulin secretion. Glucose sensitivity of all oscillation modes was increased when overnight glucose was greater than 2.8mM. To determine whether threshold shifts were a direct effect of glucose or involved secreted insulin, the KATP opener diazoxide (Dz) was coapplied with glucose to inhibit insulin secretion. The addition of Dz or the insulin receptor antagonist s961 increased islet glucose sensitivity, whereas the KATP blocker tolbutamide tended to reduce it. This suggests insulin and glucose have opposing actions on the islet glucose threshold. To test the hypothesis that the threshold shifts were due to changes in plasma membrane KATP channels, we measured cell KATP conductance, which was confirmed to be reduced by high glucose pretreatment and further reduced by Dz. Finally, treatment of INS-1 cells with glucose and Dz overnight reduced high affinity sulfonylurea receptor (SUR1) trafficking to the plasma membrane vs glucose alone, consistent with insulin increasing KATP conductance by altering channel number. The results support a role for metabolically regulated KATP channels in the maintenance of glucose homeostasis.

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