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Molecular Pharmacology

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Research ArticleArticle

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

Bharath K. Mani, Christina Robakowski, Lyubov I. Brueggemann, Leanne L. Cribbs, Abhishek Tripathi, Matthias Majetschak and Kenneth L. Byron
Molecular Pharmacology March 2016, 89 (3) 323-334; DOI: https://doi.org/10.1124/mol.115.101758
Bharath K. Mani
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Christina Robakowski
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Lyubov I. Brueggemann
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Leanne L. Cribbs
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Abhishek Tripathi
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Matthias Majetschak
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Kenneth L. Byron
Department of Molecular Pharmacology and Therapeutics (B.K.M., C.R., L.I.B., M.M., K.L.B.), Department of Cell and Molecular Physiology (L.L.C.), and Department of Surgery (A.T., M.M.), Loyola University Chicago, Maywood, Illinois
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Abstract

Kv7 (KCNQ) channels, formed as homo- or heterotetramers of Kv7.4 and Kv7.5 α-subunits, are important regulators of vascular smooth muscle cell (VSMC) membrane voltage. Recent studies demonstrate that direct pharmacological modulation of VSMC Kv7 channel activity can influence blood vessel contractility and diameter. However, the physiologic regulation of Kv7 channel activity is still poorly understood. Here, we study the effect of cAMP/protein kinase A (PKA) activation on whole cell K+ currents through endogenous Kv7.5 channels in A7r5 rat aortic smooth muscle cells or through Kv7.4/Kv7.5 heteromeric channels natively expressed in rat mesenteric artery smooth muscle cells. The contributions of specific α-subunits are further dissected using exogenously expressed human Kv7.4 and Kv7.5 homo- or heterotetrameric channels in A7r5 cells. Stimulation of Gαs-coupled β-adrenergic receptors with isoproterenol induced PKA-dependent activation of endogenous Kv7.5 currents in A7r5 cells. The receptor-mediated enhancement of Kv7.5 currents was mimicked by pharmacological agents that increase [cAMP] (forskolin, rolipram, 3-isobutyl-1-methylxanthine, and papaverine) or mimic cAMP (8-bromo-cAMP); the 2- to 4-fold PKA-dependent enhancement of currents was also observed with exogenously expressed Kv7.5 channels. In contrast, exogenously-expressed heterotetrameric Kv7.4/7.5 channels in A7r5 cells or native mesenteric artery smooth muscle Kv7.4/7.5 channels were only modestly enhanced, and homo-tetrameric Kv7.4 channels were insensitive to this regulatory pathway. Correspondingly, proximity ligation assays indicated that isoproterenol induced PKA-dependent phosphorylation of exogenously expressed Kv7.5 channel subunits, but not of Kv7.4 subunits. These results suggest that signal transduction-mediated responsiveness of vascular smooth muscle Kv7 channel subunits to cAMP/PKA activation follows the order of Kv7.5 >> Kv7.4/Kv7.5 > Kv7.4.

Footnotes

    • Received September 11, 2015.
    • Accepted December 18, 2015.
  • ↵1 Current affiliation: University of Texas Southwestern Medical Center, Dallas, Texas.

  • This work was supported by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL089564] to K.L.B., and predoctoral fellowships from the American Heart Association [09PRE2260209] and Arthur J. Schmitt Foundation to B.K.M.

  • dx.doi.org/10.1124/mol.115.101758.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (3)
Molecular Pharmacology
Vol. 89, Issue 3
1 Mar 2016
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Research ArticleArticle

PKA-Dependent Regulation of Vascular Kv7 Channels

Bharath K. Mani, Christina Robakowski, Lyubov I. Brueggemann, Leanne L. Cribbs, Abhishek Tripathi, Matthias Majetschak and Kenneth L. Byron
Molecular Pharmacology March 1, 2016, 89 (3) 323-334; DOI: https://doi.org/10.1124/mol.115.101758

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Research ArticleArticle

PKA-Dependent Regulation of Vascular Kv7 Channels

Bharath K. Mani, Christina Robakowski, Lyubov I. Brueggemann, Leanne L. Cribbs, Abhishek Tripathi, Matthias Majetschak and Kenneth L. Byron
Molecular Pharmacology March 1, 2016, 89 (3) 323-334; DOI: https://doi.org/10.1124/mol.115.101758
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