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Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia
Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152/physrev.00023.2003.— Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes. We conclude that the majority of phenotypes attributed to the monomeric G protein RhoA and mediated by its effector, Rho-kinase (ROK), reflect Ca2+ sensitization: inhibition of myosin II dephosphorylation in the presence of basal (Ca2+ dependent or independent) or increased MLCK activity. We outline the pathway from receptors through trimeric G proteins (G
q, G12, G13) to activation, by guanine nucleotide exchange factors (GEFs), from GDP · RhoA · GDI to GTP · RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane. Specific domains of GEFs interact with trimeric G proteins, and some GEFs are activated by Tyr kinases whose inhibition can inhibit Rho signaling. Inhibition of MLCP, directly by ROK or by phosphorylation of the phosphatase inhibitor CPI-17, increases phosphorylation of the myosin II regulatory light chain and thus the activity of smooth muscle and nonmuscle actomyosin ATPase and motility. We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase. Mechanisms of Ca2+ desensitization are outlined with emphasis on the antagonism between cGMP-activated kinase and the RhoA/ROK pathway. We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression. It is a potentially important therapeutic target and a subject for translational research.
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P. J. McNamara, P. Murthy, C. Kantores, L. Teixeira, D. Engelberts, T. van Vliet, B. P. Kavanagh, and R. P. Jankov Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L205 - L213. [Abstract] [Full Text] [PDF]
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R. Srinivasan, S. Forman, R. A. Quinlan, J. Ohanian, and V. Ohanian Regulation of contractility by Hsp27 and Hic-5 in rat mesenteric small arteries Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H961 - H969. [Abstract] [Full Text] [PDF]
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K. J. Allahdadi, L. C. Duling, B. R. Walker, and N. L. Kanagy Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKC{delta} Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H920 - H927. [Abstract] [Full Text] [PDF]
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M. F. Navedo, M. Nieves-Cintron, G. C. Amberg, C. Yuan, V. S. Votaw, W. J. Lederer, G. S. McKnight, and L. F. Santana AKAP150 Is Required for Stuttering Persistent Ca2+ Sparklets and Angiotensin II-Induced Hypertension Circ. Res., February 1, 2008; 102(2): e1 - e11. [Abstract] [Full Text] [PDF]
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G. A. Knock, Y. Shaifta, V. A. Snetkov, B. Vowles, S. Drndarski, J. P.T. Ward, and P. I. Aaronson Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery Cardiovasc Res, February 1, 2008; 77(3): 570 - 579. [Abstract] [Full Text] [PDF]
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M. A. Conti and R. S. Adelstein Nonmuscle myosin II moves in new directions J. Cell Sci., January 1, 2008; 121(1): 11 - 18. [Abstract] [Full Text] [PDF]
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 I. Mueed, T. Tazzeo, C. Liu, E. Pertens, Y. Zhang, I. Cybulski, L. Semelhago, J. Noora, A. Lamy, K. Teoh, et al. Isoprostanes constrict human radial artery by stimulation of thromboxane receptors, Ca2+ release, and RhoA activation J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 131 - 138. [Abstract] [Full Text] [PDF]
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 M. J. Sanderson, P. Delmotte, Y. Bai, and J. F. Perez-Zogbhi Regulation of Airway Smooth Muscle Cell Contractility by Ca2+ Signaling and Sensitivity Proceedings of the ATS, January 1, 2008; 5(1): 23 - 31. [Abstract] [Full Text] [PDF]
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R. Leguillette and A.-M. Lauzon Molecular Mechanics of Smooth Muscle Contractile Proteins in Airway Hyperresponsiveness and Asthma Proceedings of the ATS, January 1, 2008; 5(1): 40 - 46. [Abstract] [Full Text] [PDF]
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R. Schubert, D. Lidington, and S.-S. Bolz The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction Cardiovasc Res, January 1, 2008; 77(1): 8 - 18. [Abstract] [Full Text] [PDF]
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P. Komalavilas, R. B. Penn, C. R. Flynn, J. Thresher, L. B. Lopes, E. J. Furnish, M. Guo, M. A. Pallero, J. E. Murphy-Ullrich, and C. M. Brophy The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L69 - L78. [Abstract] [Full Text] [PDF]
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V. Telezhkin, T. Goecks, A. D. Bonev, G. Osol, and N. I. Gokina Decreased function of voltage-gated potassium channels contributes to augmented myogenic tone of uterine arteries in late pregnancy Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H272 - H284. [Abstract] [Full Text] [PDF]
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T. Padro, E. Pena, M. Garcia-Arguinzonis, V. Llorente-Cortes, and L. Badimon Low-density lipoproteins impair migration of human coronary vascular smooth muscle cells and induce changes in the proteomic profile of myosin light chain Cardiovasc Res, January 1, 2008; 77(1): 211 - 220. [Abstract] [Full Text] [PDF]
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D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]
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J. S. Dhaliwal, D. B. Casey, A. J. Greco, A. M. Badejo Jr., T. B. Gallen, S. N. Murthy, B. D. Nossaman, A. L. Hyman, and P. J. Kadowitz Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1306 - L1313. [Abstract] [Full Text] [PDF]
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K. J. Allahdadi, B. R. Walker, and N. L. Kanagy ROK contribution to endothelin-mediated contraction in aorta and mesenteric arteries following intermittent hypoxia/hypercapnia in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2911 - H2918. [Abstract] [Full Text] [PDF]
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S. Pellegrin and H. Mellor Actin stress fibres J. Cell Sci., October 15, 2007; 120(20): 3491 - 3499. [Abstract] [Full Text] [PDF]
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E. Ihara, L. Moffat, J. Ostrander, M. P. Walsh, and J. A. MacDonald Characterization of protein kinase pathways responsible for Ca2+ sensitization in rat ileal longitudinal smooth muscle Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G699 - G710. [Abstract] [Full Text] [PDF]
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J. F. Perez-Zoghbi and M. J. Sanderson Endothelin-induced contraction of bronchiole and pulmonary arteriole smooth muscle cells is regulated by intracellular Ca2+ oscillations and Ca2+ sensitization Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L1000 - L1011. [Abstract] [Full Text] [PDF]
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R. I. Clyman, N. Waleh, H. Kajino, C. Roman, and F. Mauray Calcium-dependent and calcium-sensitizing pathways in the mature and immature ductus arteriosus Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1650 - R1656. [Abstract] [Full Text] [PDF]
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R. J. Sandoval, E. R. Injeti, W. T. Gerthoffer, and W. J. Pearce Postnatal maturation modulates relationships among cytosolic Ca2+, myosin light chain phosphorylation, and contractile tone in ovine cerebral arteries Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2183 - H2192. [Abstract] [Full Text] [PDF]
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A. V. Somlyo Cyclic GMP Regulation of Myosin Phosphatase: A New Piece for the Puzzle? Circ. Res., September 28, 2007; 101(7): 645 - 647. [Full Text] [PDF]
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