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

2021 ◽  
Vol 118 (44) ◽  
pp. e2109441118
Author(s):  
Min Woo Sung ◽  
Zhongying Yang ◽  
Camden M. Driggers ◽  
Bruce L. Patton ◽  
Barmak Mostofian ◽  
...  
Keyword(s):  
Katp Channel ◽  
Vascular Tone ◽  
Regulatory Mechanism ◽  
Channel Activation ◽  
Autoinhibitory Domain ◽  
Tripartite Interactions ◽  
Intermediate States ◽  
Vascular Katp Channel ◽  
Dynamics Simulations ◽  
Structural Mechanisms

Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú 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 cryogenic electron microscopy 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 glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics 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 glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.

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.

Enhanced PIP3 signaling in POMC neurons causes diet-sensitive obesity as the consequence of neuronal silencing via KATP channel activation

2006 ◽  
Vol 1 (S 1) ◽  
Author(s):  
L Plum ◽  
X Ma ◽  
B Hampel ◽  
H Münzberg ◽  
M Shanabrough ◽  
...  
Keyword(s):  
Katp Channel ◽  
Channel Activation

scholarly journals Reactive oxygen species inhibit vascular KATP channel via S‐glutathionylation

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Yang Yang ◽  
Weiwei Shi ◽  
Ningren Cui ◽  
Xianfeng Chen ◽  
Yinwei Zhang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Katp Channel ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Vascular Katp Channel

52. Antipsychotics Perturb Glucose Homeostasis by Inhibiting Hypothalamic KATP Channel Activation

2019 ◽  
Vol 85 (10) ◽  
pp. S21-S22
Author(s):  
Chantel Kowalchuk ◽  
Laura Castellani ◽  
Celine Teo ◽  
Pruntha Kanagasundaram ◽  
William Brett McIntyre ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Katp Channel ◽  
Channel Activation

Relationship among NO, the KATP channel, and opioids in hypoxic pial artery dilation

1998 ◽  
Vol 275 (3) ◽  
pp. H988-H994 ◽  
Author(s):  
William M. Armstead
Keyword(s):  
Katp Channel ◽  
No Synthase ◽  
Channel Activation ◽  
Cranial Window ◽  
Pial Artery ◽  
Sequential Release ◽  
No Release ◽  
Before And After ◽  
Newborn Pigs ◽  
Synthase Inhibitor

Nitric oxide (NO), opioids, and ATP-sensitive K+(KATP) channel activation contribute to hypoxia-induced pial artery dilation. NO releasers and cGMP analogs increase opioid concentration in cerebrospinal fluid (CSF) and elicit dilation via KATPchannel activation. Opioids themselves also elicit dilation via KATP channel activation. This study was designed to investigate the relationships among the above mechanisms in hypoxic pial artery dilation using newborn pigs equipped with a closed cranial window. Cromakalim (10−8 and 10−6 M), a KATP agonist, produced dilation that was unchanged by the NO synthase inhibitor N-nitro-l-arginine (l-NNA, 10−6 and 10−3 M): 13 ± 1 and 31 ± 1 vs. 14 ± 1 and 31 ± 1% before and after 10−3 Ml-NNA. Cromakalim dilation also was not associated with increased CSF cGMP and was unchanged by the Rp diastereomer of 8-bromoguanosine 3′,5′-cyclic monophosphothioate, a cGMP antagonist. Glibenclamide (10−6 M), a KATP antagonist, attenuated hypoxic dilation but hypoxia-associated CSF cGMP release was unchanged: 457 ± 12 and 935 ± 30 vs. 458 ± 11 and 921 ± 22 fmol/ml. Coadministration ofl-NNA with glibenclamide had no further effect on the already diminished hypoxic dilation but blocked the hypoxia-associated rise in CSF cGMP. Cromakalim had no effect on CSF methionine enkephalin: 1,012 ± 28 and 1,062 ± 32 pg/ml. These data show that KATP channel agonists do not elicit dilation via NO/cGMP and do not release opioids. NO release during hypoxia also is independent of KATP channel activation. These data suggest that hypoxic dilation results from the sequential release of NO, cGMP, and opioids, which in turn activate the KATP channel.

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