Protein kinase C modulation of recombinant ATP‐sensitive K<sup>+</sup> channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B

Thorneloe, Kevin S.; Maruyama, Yoshiaki; Malcolm, A. Todd; Light, Peter E.; Walsh, Michael P.; Cole, William C.

doi:10.1113/jphysiol.2002.018101

Cited by 50 publications

(71 citation statements)

References 44 publications

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“…These results are consistent with the previous report that activation of PKCinhibits recombinant vascular K ATP channels in HEK293 cells transfected with Kir6.1 and SUR2B. 7,13,14 To determine the role of dynamin in PKC-mediated inhibition of recombinant K ATP channels, we used a dynamin mutant K44E that lacks GTPase activity and blocks dynamindependent internalization in a dominant-negative fashion. 29 PMA inhibited pinacidil-induced currents in cells cotransfected with wild-type dynamin but not in cells cotransfected with dynamin mutant K44E ( Figure 1A and 1B).…”

Section: Resultssupporting

confidence: 80%

“…11 More importantly, the modulation of recombinant Kir6.1/SUR2B but not Kir6.2/ SUR2B by PKC mimics that of native vascular K ATP channels. 13 Our data from both HEK293 cells and human dermal VSMCs further support this notion.…”

Section: Discussionsupporting

confidence: 75%

“…A previous report has shown that PKC inhibits the K ATP channel open probability possibly by increasing interburst intervals in recombinant K ATP channels composed of Kir6.1 and SUR2B, as well as K ATP channels in the rat portal vein, 13,43 indicating that a direct functional modulation of K ATP channels by PKC may contribute, in part, to the inhibitory effect of PKC on K ATP channels. Our data show that PKC-induced inhibition of K ATP channels was not completely prevented by pretreatment with M␤CD or expression of a dominant-negative dynamin mutant.…”

Section: Discussionmentioning

confidence: 99%

“…13 Several vasoconstrictors have also been shown to inhibit K ATP channels via activation of PKC. 14,15 Recent studies have revealed that Kir6.1 is mainly localized in the caveolae of aortic smooth muscle cells.…”

mentioning

confidence: 99%

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Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

et al. 2008

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Abstract-Vascular ATP-sensitive K ϩ (K ATP ) channels are critical regulators of arterial tone and, thus, blood flow in response to local metabolic needs. They are important targets for clinically used drugs to treat hypertensive emergency and angina. It is known that protein kinase C (PKC) activation inhibits K ATP channels in vascular smooth muscles. However, the mechanism by which PKC inhibits the channel remains unknown. Here we report that caveolin-dependent internalization is involved in PKC--mediated inhibition of vascular K ATP channels (Kir6.1 and SUR2B) by phorbol 12-myristate 13-acetate or angiotensin II in human embryonic kidney 293 cells and human dermal vascular smooth muscle cells. We showed that Kir6.1 substantially overlapped with caveolin-1 at the cell surface. Cholesterol depletion with methyl-␤-cyclodextrin significantly reduced, whereas overexpression of caveolin-1 largely enhanced, PKCinduced inhibition of Kir6.1/SUR2B currents. Importantly, we demonstrated that activation of PKC-caused internalization of K ATP channels, the effect that was blocked by depletion of cholesterol with methyl-␤-cyclodextrin, expression of dominant-negative dynamin mutant K44E, or knockdown of caveolin-1 with small interfering RNA. Moreover, patch-clamp studies revealed that PKC--mediated inhibition of the K ATP current induced by PMA or angiotensin II was reduced by a dynamin mutant, as well as small interfering RNA targeting caveolin-1. The reduction in the number of plasma membrane K ATP channels by PKC activation was further confirmed by cell surface biotinylation. These studies identify a novel mechanism by which the levels of vascular K ATP channels could be rapidly downregulated by internalization. This finding provides a novel mechanistic insight into how K ATP channels are regulated in vascular smooth muscle cells.

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Section: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

et al. 2008

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“…ABCC9 encodes a regulator of ATP-sensitive potassium channels that is expressed in vascular smooth muscle cells. [90][91][92][93] The protein is important for vascular tone regulation and reactivity to metabolic factors and oxidative stress. 90,[94][95][96] We hypothesize that gene variants in ABCC9 could result in chronic perturbations of the neurovascular unit leading to decrease in CBF and B-ASC pathology.…”

Section: Discussionmentioning

confidence: 99%

Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Ighodaro

Abner

Fardo

et al. 2016

J Cereb Blood Flow Metab

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Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinicalpathological correlations in the ''oldest-old'' compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n ¼ 1008) and !80 years (n ¼ 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the ! 80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n ¼ 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor.

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Molecular biology of K_ATP channels and implications for health and disease

et al. 2009

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Summary The ATP-sensitive potassium (KATP) channel is expressed in most excitable tissues and plays a critical role in numerous physiological processes by coupling intracellular energetics to electrical activity. The channel is comprised of four Kir6.x subunits associated with four regulatory sulfonylurea receptors (SUR). Intracellular ATP acts on Kir6.x to inhibit channel activity, while MgADP stimulates channel activity through SUR. Changes in the cytosolic [ATP] to [ADP] ratio thus determine channel activity. Multiple mutations in Kir6.x and SUR genes have implicated KATP channels in various diseases ranging from diabetes and hyperinsulinism to cardiac arrhythmias and cardiovascular disease. Continuing studies of channel physiology and pathology will bring new insights to the molecular basis of KATP channel function, leading to a better understanding of the role that KATP channels play in both health and disease.

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Protein kinase C modulation of recombinant ATP‐sensitive K⁺ channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B

Abstract: K. S. Thorneloe and others 70J. Physiol. 541.1

Cited by 50 publications

References 44 publications

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Molecular biology of K_ATP channels and implications for health and disease

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Protein kinase C modulation of recombinant ATP‐sensitive K+ channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B

Abstract: K. S. Thorneloe and others 70J. Physiol. 541.1

Cited by 50 publications

References 44 publications

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K + Channels

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K + Channels

Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Molecular biology of KATP channels and implications for health and disease

Contact Info

Product

Resources

About

Protein kinase C modulation of recombinant ATP‐sensitive K⁺ channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

Protein Kinase C-ε Induces Caveolin-Dependent Internalization of Vascular Adenosine 5′-Triphosphate–Sensitive K ⁺ Channels

Molecular biology of K_ATP channels and implications for health and disease