scholarly journals Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

2021 ◽  
Author(s):  
Shannon L. Macauley ◽  
Molly Stanley ◽  
Emily E Caesar ◽  
William R Moritz ◽  
Annie R Bice ◽  
...  
Keyword(s):  
Vascular Function ◽  
Katp Channel ◽  
Katp Channels ◽  
Diabetic Patients ◽  
Physiological Effects ◽  
Channel Activity ◽  
Cellular Excitability ◽  
Vascular Katp Channel ◽  
Alzheimer’S Pathology ◽  
Activity Dependent

Hyperexcitability is a defining feature of Alzheimer's disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (Aβ), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD.

Regulation of ATP-sensitive K+ channels by ATP and nucleotide diphosphate in rabbit portal vein

1994 ◽  
Vol 266 (5) ◽  
pp. H1687-H1698 ◽  
Author(s):  
M. Kamouchi ◽  
K. Kitamura
Keyword(s):  
Portal Vein ◽  
Katp Channel ◽  
Single Channel ◽  
Katp Channels ◽  
K Channel ◽  
Channel Activity ◽  
Rabbit Portal Vein ◽  
Internal Side ◽  
The Right ◽  
Single Channel Currents

The modulation of ATP-sensitive K+ (KATP)-channel activity was investigated by recording single-channel currents in isolated smooth muscle cells from rabbit portal vein. K(+)-channel openers (KCOs; pinacidil, lemakalim, and nicorandil) induced burstlike openings of single KATP channels in the cell-attached configuration. After patch excision, KATP channels showed "run-down" phenomenon in the presence of KCOs, but subsequent application of Mg-ATP (1 mM) restored KATP-channel activity. Removal of Mg-ATP resulted in transient augmentation of KATP currents, which eventually decayed out. Nucleotide diphosphates (NDPs; GDP, ADP, UDP, IDP, and CDP) also induced channel reopening in the presence of KCOs, which was markedly enhanced by addition of Mg2+ in millimolar concentrations at the internal side of the membrane. The dose-response relation between ATP and the UDP-induced KATP-channel activity was shifted to the right in the presence of Mg2+ (2 mM). These results suggest that intracellular ATP, NDPs, and Mg2+ regulate the channel state of KATP channels (operative and inoperative states) and that KCOs open KATP channels only in the operative state.

scholarly journals Anti-diabetic drug binding site in a mammalian KATP channel revealed by Cryo-EM

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Gregory M Martin ◽  
Balamurugan Kandasamy ◽  
Frank DiMaio ◽  
Craig Yoshioka ◽  
Show-Ling Shyng
Keyword(s):  
Binding Sites ◽  
Katp Channel ◽  
Katp Channels ◽  
Binding Pocket ◽  
Drug Binding ◽  
Channel Activity ◽  
Nucleotide Binding Domain ◽  
High Affinity ◽  
Drug Binding Site ◽  
First Time

Sulfonylureas are anti-diabetic medications that act by inhibiting pancreatic KATP channels composed of SUR1 and Kir6.2. The mechanism by which these drugs interact with and inhibit the channel has been extensively investigated, yet it remains unclear where the drug binding pocket resides. Here, we present a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP at 3.63 Å resolution, which reveals unprecedented details of the ATP and glibenclamide binding sites. Importantly, the structure shows for the first time that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide in our model led to reduced sensitivity to glibenclamide. Our structure provides novel mechanistic insights of how sulfonylureas and ATP interact with the KATP channel complex to inhibit channel activity.

Methylglyoxal-induced miR-223 suppresses rat vascular KATP channel activity by downregulating Kir6.1 mRNA in carbonyl stress

2020 ◽  
Vol 128-129 ◽  
pp. 106666 ◽  
Author(s):  
Xin Jin ◽  
Yang Wu ◽  
Ningren Cui ◽  
Chun Jiang ◽  
Shan-Shan Li
Keyword(s):  
Katp Channel ◽  
Carbonyl Stress ◽  
Channel Activity ◽  
Vascular Katp Channel

Blockade of Myocardial ATP-sensitive Potassium Channels by Ketamine 

1997 ◽  
Vol 87 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Seong-Hoon Ko ◽  
Sang-Kyi Lee ◽  
Young-Jin Han ◽  
Huhn Choe ◽  
Yong-Geun Kwak ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Katp Channel ◽  
Ventricular Myocytes ◽  
Katp Channels ◽  
Dependent Manner ◽  
Channel Activity ◽  
Concentration Dependent Manner ◽  
Channel Currents ◽  
Inside Out

Background The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Methods Inside-out and cell-attached configurations of patch-clamp techniques and 3 M potassium chloride-filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Results Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration-dependent manner. In the inside-out patches, the concentration of ketamine for half-maximal inhibition and the Hill coefficient were 62.9 microM and 0.54, respectively. In a concentration-dependent manner, ketamine inhibited pinacidil- and 2,4-dinitrophenol-activated KATP channels in cell-attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single-channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration-dependent manner. Conclusions Ketamine inhibited KATP channel activity in a concentration-dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.

Effects of thiol-modifying agents on KATP channels in guinea pig ventricular cells

1995 ◽  
Vol 269 (5) ◽  
pp. H1625-H1633 ◽  
Author(s):  
W. A. Coetzee ◽  
T. Y. Nakamura ◽  
J. F. Faivre
Keyword(s):  
Katp Channel ◽  
Single Channel ◽  
Katp Channels ◽  
Channel Activity ◽  
Nitrobenzoic Acid ◽  
Ventricular Cells ◽  
Channel Opening ◽  
Sh Group ◽  
Constant Potential ◽  
High Degree

ATP-sensitive K+ (KATP) channels are thought only to open during conditions of metabolic impairment (e.g., myocardial ischemia). However, the regulation of KATP channel opening during ischemia remains poorly understood. We tested whether thiol (SH) group oxidation, which is known to occur during ischemia, may be involved in KATP channel regulation. Inside-out membrane patches were voltage clamped at a constant potential (O mV) in asymmetrical K+ solutions. The effects of compounds that specifically modify SH groups [p-chloromercuri-phenylsulfonic acid (pCMPS), 5-5'-dithio-bis(2-nitrobenzoic acid) [DTNB], and thimerosal] were tested. The membrane-impermeable compound, pCMPS (> or = 5 microM), caused a quick and irreversible inhibition of KATP channel activity. The reducing agent, dl-dithiothreitol (DTT) (3 mM) was able to reverse this inhibition. DTNB (500 microM) caused a rapid, but spontaneously reversible, block of KATP channel activity. After DTNB, no change was observed in single channel conductance. Oxidized glutathione (GSSG, 3 mM) did not block KATP channel activity. Thimerosal (100-500 microM) induced a DTT-reversible block of partially rundown KATP channels, or channels that underwent complete rundown; these channels were reactivated with trypsin (1 mg/ml). Thimerosal did not block KATP channels that had a high degree of activity. However, the ATP sensitivity was decreased; the concentration of ATP needed to half-maximally inhibit the channel (Ki) was increased from 47 +/- 12 to 221 +/- 35 microM (n = 6, P < 0.05). This was not due to a spontaneous change with time.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals BAD and KATP channels regulate neuron excitability and epileptiform activity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Juan Ramón Martínez-François ◽  
María Carmen Fernández-Agüera ◽  
Nidhi Nathwani ◽  
Carolina Lahmann ◽  
Veronica L Burnham ◽  
...  
Keyword(s):  
Katp Channel ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Epileptic Seizures ◽  
Katp Channels ◽  
Brain Cell ◽  
Channel Activity

Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity.

scholarly journals Ligand-insensitive State of Cardiac ATP-sensitive K+ Channels

1998 ◽  
Vol 111 (2) ◽  
pp. 381-394 ◽  
Author(s):  
Alexey E. Alekseev ◽  
Peter A. Brady ◽  
Andre Terzic
Keyword(s):  
Kinetic Model ◽  
Katp Channel ◽  
Katp Channels ◽  
Cardiac Cell ◽  
Channel Activity ◽  
K Channels ◽  
Channel Interaction ◽  
Channel Opening ◽  
State Kinetic ◽  
Allosteric Model

The mechanism by which ATP-sensitive K+ (KATP) channels open in the presence of inhibitory concentrations of ATP remains unknown. Herein, using a four-state kinetic model, we found that the nucleotide diphosphate UDP directed cardiac KATP channels to operate within intraburst transitions. These transitions are not targeted by ATP, nor the structurally unrelated sulfonylurea glyburide, which inhibit channel opening by acting on interburst transitions. Therefore, the channel remained insensitive to ATP and glyburide in the presence of UDP. “Rundown” of channel activity decreased the efficacy with which UDP could direct and maintain the channel to operate within intraburst transitions. Under this condition, the channel was sensitive to inhibition by ATP and glyburide despite the presence of UDP. This behavior of the KATP channel could be accounted for by an allosteric model of ligand-channel interaction. Thus, the response of cardiac KATP channels towards inhibitory ligands is determined by the relative lifetime the channel spends in a ligand-sensitive versus -insensitive state. Interconversion between these two conformational states represents a novel basis for KATP channel opening in the presence of inhibitory concentrations of ATP in a cardiac cell.

scholarly journals Regulation of KATP Channel Activity by Diazoxide and MgADP

1997 ◽  
Vol 110 (6) ◽  
pp. 643-654 ◽  
Author(s):  
S.-L. Shyng ◽  
T. Ferrigni ◽  
C.G. Nichols
Keyword(s):  
Katp Channel ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Sulfonylurea Receptor ◽  
Channel Activity ◽  
Nucleotide Hydrolysis ◽  
Inward Rectifier Potassium Channel ◽  
Hydrolysis Rates ◽  
Atp Inhibition

KATP channels were reconstituted in COSm6 cells by coexpression of the sulfonylurea receptor SUR1 and the inward rectifier potassium channel Kir6.2. The role of the two nucleotide binding folds of SUR1 in regulation of KATP channel activity by nucleotides and diazoxide was investigated. Mutations in the linker region and the Walker B motif (Walker, J.E., M.J. Saraste, M.J. Runswick, and N.J. Gay. 1982. EMBO [Eur. Mol. Biol. Organ.] J. 1:945–951) of the second nucleotide binding fold, including G1479D, G1479R, G1485D, G1485R, Q1486H, and D1506A, all abolished stimulation by MgADP and diazoxide, with the exception of G1479R, which showed a small stimulatory response to diazoxide. Analogous mutations in the first nucleotide binding fold, including G827D, G827R, and Q834H, were still stimulated by diazoxide and MgADP, but with altered kinetics compared with the wild-type channel. None of the mutations altered the sensitivity of the channel to inhibition by ATP4−. We propose a model in which SUR1 sensitizes the KATP channel to ATP inhibition, and nucleotide hydrolysis at the nucleotide binding folds blocks this effect. MgADP and diazoxide are proposed to stabilize this desensitized state of the channel, and mutations at the nucleotide binding folds alter the response of channels to MgADP and diazoxide by altering nucleotide hydrolysis rates or the coupling of hydrolysis to channel activation.

scholarly journals Elevation in Intracellular Long-Chain Acyl-Coenzyme A Esters Lead to Reduced β-Cell Excitability via Activation of Adenosine 5′-Triphosphate-Sensitive Potassium Channels

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3679-3687 ◽  
Author(s):  
Nicola J. Webster ◽  
Gavin J. Searle ◽  
Patrick P. L. Lam ◽  
Ya-Chi Huang ◽  
Michael J. Riedel ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Katp Channel ◽  
Katp Channels ◽  
Channel Activity ◽  
Β Cells ◽  
Β Cell ◽  
Cell Excitability ◽  
Chain Acyl ◽  
Long Chain

Closure of pancreatic β-cell ATP-sensitive potassium (KATP) channels links glucose metabolism to electrical activity and insulin secretion. It is now known that saturated, but not polyunsaturated, long-chain acyl-coenyzme A esters (acyl-CoAs) can potently activate KATP channels when superfused directly across excised membrane patches, suggesting a plausible mechanism to account for reduced β-cell excitability and insulin secretion observed in obesity and type 2 diabetes. However, reduced β-cell excitability due to elevation of endogenous saturated acyl-CoAs has not been confirmed in intact pancreatic β-cells. To test this notion directly, endogenous acyl-CoA levels were elevated within primary mouse β-cells using virally delivered overexpression of long-chain acyl-CoA synthetase-1 (AdACSL-1), and the effects on β-cell KATP channel activity and cell excitability was assessed using the perforated whole-cell and cell-attached patch-clamp technique. Data indicated a significant increase in KATP channel activity in AdACSL-1-infected β-cells cultured in medium supplemented with palmitate/oleate but not with the polyunsaturated fat linoleate. No changes in the ATP/ADP ratio were observed in any of the groups. Furthermore, AdACSL-1-infected β-cells (with palmitate/oleate) showed a significant decrease in electrical responsiveness to glucose and tolbutamide and a hyperpolarized resting membrane potential at 5 mm glucose. These results suggest a direct link between intracellular fatty ester accumulation and KATP channel activation, which may contribute to β-cell dysfunction in type 2 diabetes.

scholarly journals Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides

2021 ◽  
Author(s):  
Min Woo Sung ◽  
Zhongying Yang ◽  
Bruce L Patton ◽  
Barmak Mostofian ◽  
John Russo ◽  
...  
Keyword(s):  
Katp Channel ◽  
Vascular Tone ◽  
Regulatory Mechanism ◽  
Katp Channels ◽  
Md Simulations ◽  
Channel Activation ◽  
Autoinhibitory Domain ◽  
Tripartite Interactions ◽  
Vascular Katp Channel ◽  
Structural Mechanisms

Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantu syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined the first cryoEM structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational propeller and quatrefoil geometries surrounding their Kir6.1 core. The previously unseen ED-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. MD simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated and MgADP-bound activated conformations wherein the ED-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.

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