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(Circulation Research. 2007;101:1078.)
© 2007 American Heart Association, Inc.

Editorials

cGMP-Dependent Protein Kinase I and Smooth Muscle Relaxation

A Tale of Two Isoforms

Howard K. Surks

From the Tufts-New England Medical Center, Boston, Mass.

Correspondence to Howard K. Surks, Tufts-New England Med Center, Molecular Cardiology Research Institute, 750 Washington St, Box 80, Boston, MA 02111. E-mail hsurks@tufts-nemc.org

See related article, pages 1096–1103

Key Words: myosin phosphatase • RhoA • smooth muscle • GMP-dependent protein kinase I • inositol 1,4,5 triphosphate receptor-associated cGMP kinase substrate • myosin phosphatase-rho interacting protein • regulator of G protein signaling 2

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The maintenance of vascular tone is central to the regulation of blood pressure and tissue perfusion and plays a role in the pathogenesis of hypertension and atherosclerosis. Vascular tone is determined by the balance of vasodilator and vasoconstrictor stimuli. After several decades of research, the NO/cGMP/cGMP-dependent protein kinase (cGK) pathway is now recognized as an important mediator of vasodilation. However, the mechanisms by which cGK causes smooth muscle relaxation continue to be an important question.

Smooth muscle contraction and relaxation are tightly coupled to the phosphorylation and dephosphorylation, respectively, of the regulatory myosin light chain.¹ Myosin light chain phosphorylation state is determined by the relative activities of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP). MLCK phosphorylates MLC leading to contraction,² and MLCP dephosphorylates MLC, leading to relaxation³ (Figure). Both MLCK and MLCP activities are highly regulated. MLCK activity is activated by the binding of calcium/calmodulin and thus is the primary mechanism linking intracellular calcium concentration to smooth muscle contractility.⁴ MLCP activity is regulated by both vasodilator and vasoconstrictor stimuli, and is therefore responsible for much of the calcium-independent regulation of contractility (reviewed in⁵).

View larger version (56K):   Figure. MLC phosphorylation determines smooth muscle contractility. Contractile agonists lead to inositol 1,4,5 triphosphate (IP3) production or activation of RhoA (RhoA-GTP). IP3 binding to its receptor in the sarcoplasmic reticulum leads to release of Ca2+. Ca2+/calmodulin binds to and activates MLCK, which in turn phosphorylates MLC (calcium-dependent contraction). Activated RhoA binds to and activates ROCK, leading to . . . [Full Text of this Article]

Related Article:

Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle–Specific Expression of Either Isozyme

Silke Weber, Dominik Bernhard, Robert Lukowski, Pascal Weinmeister, René Wörner, Jörg W. Wegener, Nadejda Valtcheva, Susanne Feil, Jens Schlossmann, Franz Hofmann, and Robert Feil
Circ. Res. 2007 101: 1096-1103. [Abstract] [Full Text] [PDF]

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