Copyright © 2007, European Society of Cardiology
Angiotensin II-activated protein kinase C targets caveolae to inhibit aortic ATP-sensitive potassium channels
aBiosciences Building, School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom
bDepartment of Cell Physiology ... Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, United Kingdom
cPreclinical Veterinary Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZJ, United Kingdom
*Corresponding author. Tel.: +44 151 795 4462; fax: +44 151 795 4404. c.dart{at}liv.ac.uk
Objective The vasoconstrictor angiotensin II (Ang II) acts at Gq/11-coupled receptors to suppress ATP-sensitive potassium (KATP) channel activity via activation of protein kinase C (PKC). The aim of this study was to determine the PKC isoforms involved in the Ang II-induced inhibition of aortic KATP channel activity and to investigate potential mechanisms by which these isoforms specifically target these ion channels.
Methods and results We show that the inhibitory effect of Ang II on pinacidil-evoked whole-cell rat aortic KATP currents persists in the presence of Gö6976, an inhibitor of the conventional PKC isoforms, but is abolished by intracellular dialysis of a selective PKC
translocation inhibitor peptide. This suggests that PKC-dependent inhibition of aortic KATP channels by Ang II arises exclusively from the activation and translocation of PKC. Using discontinuous sucrose density gradients and Western blot analysis, we show that Ang II induces the translocation of PKC to cholesterol-enriched rat aortic smooth muscle membrane fractions containing both caveolin, a protein found exclusively in caveolae, and Kir6.1, the pore-forming subunit of the vascular KATP channel. Immunogold electron microscopy of rat aortic smooth muscle plasma membrane sheets confirms both the presence of Kir6.1 in morphologically identifiable regions of the membrane rich in caveolin and Ang II-evoked migration of PKC to these membrane compartments.
Conclusions Ang II induces the recruitment of the novel PKC isoform, PKC, to arterial smooth muscle caveolae. This translocation allows PKC access to KATP channels compartmentalized within these specialized membrane microdomains and highlights a potential role for caveolae in targeting PKC isozymes to an ion channel effector.
KEYWORDS Angiotensin; K-ATP channel; Protein kinase C; Smooth muscle; Arteries; Caveolae; Signal transduction
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