AMPK Dilates Resistance Arteries via Activation of SERCA and BK
            <sub>Ca</sub>
            Channels in Smooth Muscle

Schneider, Holger; Schubert, Kai; Blodow, Stephanie; Kreutz, Claus-Peter; Erdogmus, Serap; Wiedenmann, Margarethe; Qiu, Jian; Fey, Theres; Ruth, Peter; Lubomirov, Lubomir T.; Pfitzer, Gabriele; Schnitzler, Michael Mederos y; Hardie, D. Grahame; Gudermann, Thomas; Pohl, Ulrich

doi:10.1161/hypertensionaha.115.05514

Cited by 58 publications

(70 citation statements)

References 42 publications

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“…16 However, de-endothelialized mouse arteries, preconstricted with 125 mmol/L K + and pretreated with the SERCA inhibitor thapsigargin still showed a prominent dilation on stimulation with PT1 ( Figure 1A). In contrast to the dilations already described, 16 these dilations developed slowly and reached a maximum of 59.3±3.3% only after 40 minutes, compared with 4.4±3.8% in time controls.…”

Section: Resultsmentioning

confidence: 95%

“…The concentrations of both compounds used were equally effective to induce short-term dilation of norepinephrine preconstricted arteries. 16 Wash-out of the AMPK activators partly reversed their inhibitory effect (not shown). The [Ca 2+ ] i response to the stepwise increase of extracellular Ca 2+ concentrations was the same under all 3 conditions, suggesting a reduction of Ca 2+ sensitivity caused by AMPK activation ( Figure 1C; Online Figure II).…”

Section: Reduced Ca 2+ Sensitivity Of Vsm Cell After Ampk Activationmentioning

confidence: 91%

“…16 For technical reasons, MLC 20 Ser 19 phosphorylation was expressed relative to actin rather than to MLC 20 total, which would have allowed to analyze the relevant ratio of both proteins. To exclude that a change in MLC 20 phosphorylation might be masked if PT1 affected the expression level of MLC 20 , we normalized MLC 20 total to myosin heavy chain from the same gel.…”

Section: What New Information Does This Article Contribute?mentioning

confidence: 99%

“…AMPK can induce smooth muscle relaxation directly by a decrease of [Ca 2+ ] i or of Ca 2+ sensitivity. [16][17][18][19][20][21] In a recent study, we identified AMPK as a new potential upstream kinase of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) regulator phospholamban and a regulator of the BK Ca (large conductance calcium-activated potassium) channel in microvascular smooth muscle. Nonetheless, there was still an additional, slowly developing vasodilation, which was probably Ca 2+ -independent because it was still observed after inhibition of SERCA BK Ca .…”

mentioning

confidence: 99%

“…Nonetheless, there was still an additional, slowly developing vasodilation, which was probably Ca 2+ -independent because it was still observed after inhibition of SERCA BK Ca . 16 In view of recent studies, which have implicated AMPK in the regulation of actin cytoskeletal dynamics and reorganization at the plasma membrane, [22][23][24][25][26][27] it may be hypothesized that AMPK is inducing Ca 2+ -independent dilation by reducing actin filament size or number similar as observed during reduction of cell migration. However, AMPK has also been reported to interfere with upstream regulators of the myosin phosphatase and to phosphorylate MLCK, thereby inhibiting its activity.…”

mentioning

confidence: 99%

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The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Schubert

Qiu

Blodow

et al. 2017

Circulation Research

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2+ sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca2+ . This may be particularly important in states requiring maintained dilation, such as hypoxia. AMP-related kinase (AMPK) is an important cellular energy sensor in VSM. Regulation of Ca 2+ sensitivity usually is attributed to myosin light chain phosphatase activity, but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown.Objective: To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca 2+ desensitization of VSM contractile apparatus. Methods and Results: AMPK induced a slowly developing dilation at unchanged cytosolic Ca2+ levels in potassium chloride-constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of myosin light chain phosphatase regulatory subunit. Using ultracentrifugation and confocal microscopy, we found that AMPK induced depolymerization of F-actin (filamentous actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the midcellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Coimmunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein.

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Section: Resultsmentioning

confidence: 95%

Section: Reduced Ca 2+ Sensitivity Of Vsm Cell After Ampk Activationmentioning

confidence: 91%

Section: What New Information Does This Article Contribute?mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Schubert

Qiu

Blodow

et al. 2017

Circulation Research

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The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells

Ottolini

Sonkusare

2021

Comprehensive Physiology

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The contractile state of resistance arteries and arterioles is a crucial determinant of blood pressure and blood flow. Physiological regulation of arterial contractility requires constant communication between endothelial and smooth muscle cells. Various Ca 2+ signals and Ca 2+ -sensitive targets ensure dynamic control of intercellular communications in the vascular wall. The functional effect of a Ca 2+ signal on arterial contractility depends on the type of Ca 2+ -sensitive target engaged by that signal. Recent studies using advanced imaging methods have identified the spatiotemporal signatures of individual Ca 2+ signals that control arterial and arteriolar contractility. Broadly speaking, intracellular Ca 2+ is increased by ion channels and transporters on the plasma membrane and endoplasmic reticular membrane. Physiological roles for many vascular Ca 2+ signals have already been confirmed, while further investigation is needed for other Ca 2+ signals. This article focuses on endothelial and smooth muscle Ca 2+ signaling mechanisms in resistance arteries and arterioles. We discuss the Ca 2+ entry pathways at the plasma membrane, Ca 2+ release signals from the intracellular stores, the functional and physiological relevance of Ca 2+ signals, and their regulatory mechanisms. Finally, we describe the contribution of abnormal endothelial and smooth muscle Ca 2+ signals to the pathogenesis of vascular disorders.

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Inhibition of voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells by the atypical antipsychotic agent sertindole

Zhuang,

Mun,

Park

et al. 2023

J of Applied Toxicology

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The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage‐dependent K+ (Kv) potassium channels are well‐established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose‐dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 μM. Although sertindole did not cause a change in the steady‐state activation curve, it did lead to a negative shift in the steady‐state inactivation curve. The application of 1‐ or 2‐Hz train pulses failed to alter the sertindole‐induced inhibition of Kv channels, suggesting use‐independent effects of the drug. The inhibitory response to sertindole was significantly diminished by pretreatment with a Kv1.5 inhibitor but not by Kv2.1 and Kv7 subtype inhibitors. These findings demonstrate the sertindole dose‐dependent and use‐independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady‐state inactivation curves. Therefore, the use of sertindole as an antipsychotic drug may have adverse effects on the cardiovascular system.

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AMPK Dilates Resistance Arteries via Activation of SERCA and BK _Ca Channels in Smooth Muscle

Cited by 58 publications

References 42 publications

The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells

Inhibition of voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells by the atypical antipsychotic agent sertindole

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AMPK Dilates Resistance Arteries via Activation of SERCA and BK Ca Channels in Smooth Muscle

Cited by 58 publications

References 42 publications

The AMP-Related Kinase (AMPK) Induces Ca 2+ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

The AMP-Related Kinase (AMPK) Induces Ca 2+ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells

Inhibition of voltage‐dependent K+ channels in rabbit coronary arterial smooth muscle cells by the atypical antipsychotic agent sertindole

Contact Info

Product

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AMPK Dilates Resistance Arteries via Activation of SERCA and BK _Ca Channels in Smooth Muscle

The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Inhibition of voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells by the atypical antipsychotic agent sertindole