This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 52/3/499    most recent HYPERTENSIONAHA.108.110817v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jiao, J. Articles by Hu, K. Search for Related Content PubMed PubMed Citation Articles by Jiao, J. Articles by Hu, K. Related Collections ACE/Angiotension receptors Hypertension - basic studies Ion channels/membrane transport Related Article

(Hypertension. 2008;52:499.)
© 2008 American Heart Association, Inc.

Original Articles

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

Jundong Jiao; Vivek Garg; Baofeng Yang; Terry S. Elton; Keli Hu

From the Division of Pharmacology, College of Pharmacy (J.J., V.G., T.S.E., K.H.), and Davis Heart and Lung Research Institute (T.S.E.), Ohio State University, Columbus; and the Department of Pharmacology (B.Y.), Harbin Medical University, Harbin, Heilongjiang, China.

Correspondence to Keli Hu, 530 Parks Hall, Division of Pharmacology, College of Pharmacy, 500 W 12th Ave, Ohio State University, Columbus, OH 43210. E-mail hu.175{at}osu.edu

Vascular ATP-sensitive K⁺ (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-β-cyclodextrin significantly reduced, whereas overexpression of caveolin-1 largely enhanced, PKC-induced 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-β-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.

Key Words: K_ATP • ion channel • caveolin-1 • angiotensin II • dynamin

Related Article:

Vanishing Act: Protein Kinase C–Dependent Internalization of Adenosine 5'-Triphosphate–Sensitive K⁺ Channels

William F. Jackson
Hypertension 2008 52: 470-472. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				R. D. Rainbow, R. I. Norman, D. E. Everitt, J. L. Brignell, N. W. Davies, and N. B. Standen Endothelin-I and angiotensin II inhibit arterial voltage-gated K+ channels through different protein kinase C isoenzymes Cardiovasc Res, August 1, 2009; 83(3): 493 - 500. [Abstract] [Full Text] [PDF]

				W. F. Jackson Vanishing Act: Protein Kinase C-Dependent Internalization of Adenosine 5'-Triphosphate-Sensitive K+ Channels Hypertension, September 1, 2008; 52(3): 470 - 472. [Full Text] [PDF]