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Physiol. Rev. 83: 1325-1358, 2003; doi:10.1152/physrev.00023.2003
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Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

ANDREW P. SOMLYO and AVRIL V. SOMLYO

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{alpha}q, G{alpha}12, G{alpha}13) 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.


Address for reprint requests and other correspondence: A. P. Somlyo, Dept. of Molecular Physiology and Biological Physics, Univ. of Virginia, PO Box 800736, Charlottesville, VA 22908-0736 (E-mail: aps2n{at}virginia.edu).




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Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction
Am J Physiol Cell Physiol, September 1, 2008; 295(3): C576 - C587.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
A.C. Montezano, G.E. Callera, A. Yogi, Y. He, R.C. Tostes, G. He, E.L. Schiffrin, and R.M. Touyz
Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways
Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1511 - 1518.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
Y. Mizuno, E. Isotani, J. Huang, H. Ding, J. T. Stull, and K. E. Kamm
Myosin light chain kinase activation and calcium sensitization in smooth muscle in vivo
Am J Physiol Cell Physiol, August 1, 2008; 295(2): C358 - C364.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
C. J. Clarke, S. Forman, J. Pritchett, V. Ohanian, and J. Ohanian
Phospholipase C-{delta}1 modulates sustained contraction of rat mesenteric small arteries in response to noradrenaline, but not endothelin-1
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H826 - H834.
[Abstract] [Full Text] [PDF]


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Mol. Cell. ProteomicsHome page
E. Yohannes, J. Chang, G. J. Christ, K. P. Davies, and M. R. Chance
Proteomics Analysis Identifies Molecular Targets Related to Diabetes Mellitus-associated Bladder Dysfunction
Mol. Cell. Proteomics, July 1, 2008; 7(7): 1270 - 1285.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
D. Schaafsma, I. S. T. Bos, A. B. Zuidhof, J. Zaagsma, and H. Meurs
The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation
Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L214 - L219.
[Abstract] [Full Text] [PDF]


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Postgrad. Med. J.Home page
B Wojciak-Stothard
New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling
Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353.
[Abstract] [Full Text] [PDF]


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IOVSHome page
P. V. Rao, Y. K. Peterson, T. Inoue, and P. J. Casey
Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork
Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2464 - 2471.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Renal Physiol.Home page
K. Takeya, K. Loutzenhiser, M. Shiraishi, R. Loutzenhiser, and M. P. Walsh
A highly sensitive technique to measure myosin regulatory light chain phosphorylation: the first quantification in renal arterioles
Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1487 - F1492.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
L. Chen, J. J. Zhang, and X.-Y. Huang
cAMP Inhibits Cell Migration by Interfering with Rac-induced Lamellipodium Formation
J. Biol. Chem., May 16, 2008; 283(20): 13799 - 13805.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
W. G. Wier, M. A. Rizzo, H. Raina, and J. Zacharia
A technique for simultaneous measurement of Ca2+, FRET fluorescence and force in intact mouse small arteries
J. Physiol., May 15, 2008; 586(10): 2437 - 2443.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
H. Yasue, Y. Mizuno, E. Harada, T. Itoh, H. Nakagawa, M. Nakayama, H. Ogawa, S. Tayama, T. Honda, S. Hokimoto, et al.
Effects of a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Fluvastatin, on Coronary Spasm After Withdrawal of Calcium-Channel Blockers
J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1742 - 1748.
[Abstract] [Full Text] [PDF]


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Am. J. Respir. Cell Mol. Bio.Home page
P. Delmotte and M. J. Sanderson
Effects of Albuterol Isomers on the Contraction and Ca2+ Signaling of Small Airways in Mouse Lung Slices
Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 524 - 531.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
P. J. Dougherty, M. J. Davis, D. C. Zawieja, and M. Muthuchamy
Calcium sensitivity and cooperativity of permeabilized rat mesenteric lymphatics
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1524 - R1532.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
H. H. Wang, H. Tanaka, X. Qin, T. Zhao, L.-H. Ye, T. Okagaki, T. Katayama, A. Nakamura, R. Ishikawa, S. E. Thatcher, et al.
Blebbistatin inhibits the chemotaxis of vascular smooth muscle cells by disrupting the myosin II-actin interaction
Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2060 - H2068.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
B. R. S. Broughton, B. R. Walker, and T. C. Resta
Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries
Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L797 - L806.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. Chiba, J. Arima, H. Sakai, and M. Misawa
Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma
Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L705 - L713.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
N. Villalba, E. Stankevicius, U. Simonsen, and D. Prieto
Rho kinase is involved in Ca2+ entry of rat penile small arteries
Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1923 - H1932.
[Abstract] [Full Text] [PDF]


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J. Cell Sci.Home page
J. T. Smyth, W. I. DeHaven, G. S. Bird, and J. W. Putney Jr
Ca2+-store-dependent and -independent reversal of Stim1 localization and function
J. Cell Sci., March 15, 2008; 121(6): 762 - 772.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
S. Rattan and C. A. Patel
Selectivity of ROCK inhibitors in the spontaneously tonic smooth muscle
Am J Physiol Gastrointest Liver Physiol, March 1, 2008; 294(3): G687 - G693.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
C. Morin, C. Guibert, M. Sirois, V. Echave, M. M. Gomes, and E. Rousseau
Effects of {omega}-hydroxylase product on distal human pulmonary arteries
Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1435 - H1443.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
P. D. Smith, S. E. Brett, K. D. Luykenaar, S. L. Sandow, S. P. Marrelli, E. J. Vigmond, and D. G. Welsh
KIR channels function as electrical amplifiers in rat vascular smooth muscle
J. Physiol., February 15, 2008; 586(4): 1147 - 1160.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
D. Umeda, S. Yano, K. Yamada, and H. Tachibana
Green Tea Polyphenol Epigallocatechin-3-gallate Signaling Pathway through 67-kDa Laminin Receptor
J. Biol. Chem., February 8, 2008; 283(6): 3050 - 3058.
[Abstract] [Full Text] [PDF]


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Am. J. Respir. Cell Mol. Bio.Home page
C. Morin, M. Sirois, V. Echave, M. M. Gomes, and E. Rousseau
EET Displays Anti-Inflammatory Effects in TNF-{alpha} Stimulated Human Bronchi: Putative Role of CPI-17
Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 192 - 201.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
S. K. Sarna
Are interstitial cells of Cajal plurifunction cells in the gut?
Am J Physiol Gastrointest Liver Physiol, February 1, 2008; 294(2): G372 - G390.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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Am. J. Physiol. Heart Circ. Physiol.Home page
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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Am. J. Physiol. Heart Circ. Physiol.Home page
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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Circ. Res.Home page
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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Cardiovasc ResHome page
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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J. Cell Sci.Home page
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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J. Thorac. Cardiovasc. Surg.Home page
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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Proc Am Thorac SocHome page
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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