Vanishing act: protein kinase C-dependent internalization of adenosine 5'-triphosphate-sensitive K+ channels.

Potassium channels play an important role in the regulation of vascular smooth muscle tone and, thus, contribute to the regulation of blood pressure, blood flow, and microvascular exchange.1 These channels importantly participate in the determination of vascular smooth muscle cell (VSMC) membrane potential,1,2 which, in turn, controls Ca influx through voltage-gated Ca channels1,2 and has been implicated in the control of Ca release and Ca sensitivity of VSMCs.1 VSMCs express a diverse array of K channels that contribute to the regulation of VSMC function,1 including 1 type of vascular ATPsensitive K (KATP) channels.2,3 KATP channels consist of a tetramer of -pore–forming subunits from the KIR6.X family of inwardly rectifying K channels, along with complimentary sulfonylurea receptor (SUR) subunits that are members of the ATP-binding cassette family of proteins.2 The SUR subunits are essential for normal trafficking of KATP channels, modulate channel function, and are the binding sites for sulfonylurea antagonists of these channels, such as glibenclamide.2 Vascular smooth muscle KATP channels appear to be composed of KIR6.1 and SUR2B subunits,2 although some VSMCs may also express KATP channels composed of KIR6.2/SUR2B.3 As originally described, KATP channels open during hypoxia or ischemic conditions when cellular ATP levels fall, decreasing cell excitability and protecting energy-limited cells.2 However, both in vitro and in vivo studies suggest that VSMC KATP channels may be open under resting conditions and contribute to the regulation of VSMC membrane potential and vascular tone.1,2 Importantly, the activity of KATP channels can be modulated by a number of physiologically relevant vasoactive substances and conditions. As their name implies, KATP channels may be activated by decreases in intracellular ATP and appear be important sensors of the metabolic status of cells, opening during ischemic or hypoxic conditions to promote vasodilation and an increase in blood flow and oxygen delivery.1,2 KATP channels also are modulated by a plethora of additional intracellular signals including ADP, H , and Ca .1,2 cAMP, acting through protein kinase A, activates VSMC KATP channels such that vasodilators including isoproterenol, adenosine, prostaglandin I2, and calcitonin-gene-related-peptide act, in part, through these channels.1,2 In contrast, vasoconstrictors that act through G protein–coupled receptors such as norepinephrine, phenylephrine, serotonin, histamine, neuropeptide Y, endothelin, vasopressin, and angiotensin II all inhibit VSMC KATP channels.1,2 Vasoconstrictor-induced inhibition of KATP channels results from 3 mechanisms: Ca -dependent activation of the phosphatase, calcineurin (protein phosphatase 2B or protein phosphatase 3),4 Gi/o-mediated inhibition of constitutive adenylate cyclase activity,5 and activation of protein kinase C (PKC)3,5,6 (see the Figure). The study by Jiao et al7 in this issue of Hypertension confirms and extends these studies, demonstrating an important role for PKCin the inhibition of KATP channel currents in both human embryonic kidney (HEK) cells and VSMCs by phorbol esters and angiotensin II. PKC has been implicated in vasoconstrictor-induced inhibition of KATP channels for more than a decade (see Reference 5 for older literature). Previous studies identified PKCas an important isoform in VSMCs and indicated that targeting of KATP channels and PKCto caveolae was essential in this interaction.6 However, the mechanism by which PKCinhibits KATP channels remained unclear. Jiao et al7 present data showing that PKC-induced inhibition of KATP channels, both in HEK cells and native VSMCs, involves caveolin-dependent internalization of the channels (Figure). They showed that PKC-dependent inhibition of KIR 6.1/SUR2B channels expressed in HEK cells, as well as KATP channels expressed in dermal VSMCs, was associated with redistribution of the channels from the plasma membrane into the cytosol and that both inhibition of KATP channel currents and internalization were reduced by expression of a dominant-negative form of dynamin. Disruption of caveolae by removal of membrane cholesterol with methyl-cyclodextrin prevented, whereas overexpression of caveolin-1 potentiated, the inhibitory effects of PKC in HEK cells. Similarly, in VSMCs, Jiao et al7 showed that angiotensin II–induced inhibition of pinacidil-stimulated KATP currents and stimulation of KATP channel internalization could be blunted by PKC antagonists, expression of a dominant-negative form of dynamin, or siRNA knockdown of caveolin-1. These experiments show that rapid, PKCdependent internalization of VSMC KATP channels may underlie PKC-dependent inhibition of KATP channel currents, adding to our understanding of the regulation of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology and Toxicology, Michigan State University, East Lansing. Correspondence to William F. Jackson, Pharmacology and Toxicology, Michigan State University, B-420 Life Sciences Building, East Lansing, MI 48824. E-mail [email protected] (Hypertension. 2008;52:470-472.) © 2008 American Heart Association, Inc.