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Research ArticleCARDIOVASCULAR

Role of Protein Kinase Cζ and Calcium Entry in KCl-Induced Vascular Smooth Muscle Calcium Sensitization and Feedback Control of Cellular Calcium Levels

Paul H. Ratz and Amy S. Miner
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 399-408; DOI: https://doi.org/10.1124/jpet.108.142422
Paul H. Ratz
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Amy S. Miner
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Abstract

The degree of tonic force (F) maintenance induced in vascular smooth muscle upon K+ depolarization with 110 mM KCl can be greatly reduced by inhibition of rhoA kinase (ROCK). We explored the possibility that a protein kinase C (PKC) isotype may also play a role in causing KCl-induced Ca2+ sensitization. In isometric rings of rabbit artery, the PKC inhibitors, Go-6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione), GF-109203X (2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide), and a cell-permeable (myristoylated) pseudosubstrate inhibitor of PKCζ (PIPKCζ) inhibited KCl-induced tonic F. A myristoylated pseudosubstrate inhibitor of PKCα/β that inhibited phorbol dibutyrate-induced F slightly potentiated KCl-induced tonic F and attenuated 30 mM KCl-induced F. Although the ROCK inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)-sulfonyl]-hexahydro-1H-1,4-diazepine dihydrochloride], reduced basal phosphorylation of myosin light-chain phosphatase-targeting subunit at Thr853 (MYPT1-pT853), 3 and 10 μM GF-109203X inhibited only KCl-stimulated phosphorylation, not basal MYPT1-pT853. In fura-2-loaded tissues, GF-109203X and PIPKCζ elevated basal [Ca2+]i (calcium) and potentiated KCl-induced tonic increases in calcium while reducing KCl-induced tonic increases in F. Blockade by nifedipine of Ca2+ entry through voltage-operated Ca2+ channels reduced KCl-induced Ca2+ sensitization and KCl-stimulated but not basal MYPT1-pT853. These data together support a model in which ROCK and PKCζ are constitutively active and function in “resting” muscle to regulate the basal levels of MYPT1-pT853 and calcium, respectively. In this model, KCl-induced increases in calcium activate PKCζ to feed forward and cause additional MYPT1-pT853 above that induced by constitutive ROCK, permitting Ca2+ sensitization and strong F maintenance. Active PKCζ also feeds back to attenuate the degree of KCl-induced increases in calcium.

Footnotes

  • This work was supported by the National Institutes of Health [Grant R01-HL61320] and by the American Heart Association.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.142422.

  • ABBREVIATIONS: F, isometric force; MLCK, myosin light-chain kinase; MLCp, myosin light-chain phosphorylation; MLCP, myosin light-chain phosphatase; GPCR, G protein-coupled receptor; ROCK, rhoA kinase; PKC, protein kinase C; VOCC, voltage-operated calcium channel; GF-109203X, 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide; Y-27632, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecar boxamide dihydrochloride; HA-1077, 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride; H-1152, (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-hexahydro-1H-1,4-diazepine dihydrochloride; PSS, physiological saline solution; MOPS, 4-morpholinepropanesulfonic acid; Lo, optimal length for muscle contraction; Fo, maximal force at the optimal length for muscle contraction; MYPT1-pT853, myosin light-chain phosphatase-targeting subunit Thr853 phosphorylation; PBS, phosphate-buffered saline; BSA, bovine serum albumin; Go-6983, 3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione; Go-6976, 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile; DMSO, dimethyl sulfoxide; PIPKC, myristoylated pseudosubstrate inhibitor of PKC; PE, phenylephrine; PD98059, 2′-amino-3′-methoxyflavone; VSM, vascular smooth muscle; CPI-17, 17-kDa protein kinase C-dependent MLCP inhibitor.

    • Received June 16, 2008.
    • Accepted November 13, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleCARDIOVASCULAR

Role of Protein Kinase Cζ and Calcium Entry in KCl-Induced Vascular Smooth Muscle Calcium Sensitization and Feedback Control of Cellular Calcium Levels

Paul H. Ratz and Amy S. Miner
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 399-408; DOI: https://doi.org/10.1124/jpet.108.142422

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Research ArticleCARDIOVASCULAR

Role of Protein Kinase Cζ and Calcium Entry in KCl-Induced Vascular Smooth Muscle Calcium Sensitization and Feedback Control of Cellular Calcium Levels

Paul H. Ratz and Amy S. Miner
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 399-408; DOI: https://doi.org/10.1124/jpet.108.142422
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