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(Circulation Research. 2007;101:645.)
© 2007 American Heart Association, Inc.

Editorials

Cyclic GMP Regulation of Myosin Phosphatase

A New Piece for the Puzzle?

Avril V. Somlyo

From the Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville.

Correspondence to Avril V. Somlyo, Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, 22908. E-mail avs5u@virginia.edu

See related article, pages 712–722

Key Words: smooth muscle • Ca²⁺-desensitization • cyclic GMP

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

The contractile state of smooth muscle (SM) reflects the ratio of activities of myosin light-chain kinase (MLCK) and myosin light chain phosphatase (MLCP), which determines the extent of regulatory light chain (RLC) phosphorylation and actin-activated myosin II activity and can be changed by modulating the activities of the calcium-calmodulin–dependent MLCK or of MLCP. Agonists through G protein–coupled receptors, which activate the small G protein RhoA and its effector, Rho-kinase (ROK), results in inhibitory phosphorylation of the regulatory subunit (MYPT1) of MLCP leading to an increase in RLC phosphorylation and force independent of a change in [Ca²⁺]_i, a process termed Ca²⁺ sensitization (reviewed in¹). The importance of regulation of MLCP activity has focused attention on potential phosphorylation sites² on MYPT1 especially Thr-696, Thr-853, Ser-695, and Ser-852 (numbering for the human MW133 isoform) (Figure) but the physiologically relevant sites remain to be fully understood. CPI-17, found in some SMs is another potential mediator of Ca²⁺ sensitization, which on phosphorylation by a variety of kinases inhibits the MLCP catalytic subunit, PP1c resulting in Ca²⁺-sensitized force independent of phosphorylation of MYPT1.³ Conversely, cyclic nucleotides can relax Ca²⁺-sensitized force and reduce RLC phosphorylation through activation or disinhibition of MLCP activity leading to Ca²⁺ desensitization. Early studies showed that cyclic GMP decreased Ca²⁺ sensitivity⁴ and reversed agonist-induced Ca²⁺-sensitized force at constant Ca²⁺.^5,6 Urocortin-induced Ca²⁺ desensitization through PKA activation leads to a decrease in both Thr-696 and Thr-853.⁷ Direct phosphorylation of MYPT1 has been shown for both PKA . . . [Full Text of this Article]

Related Article:

cGMP-Dependent Relaxation of Smooth Muscle Is Coupled With the Change in the Phosphorylation of Myosin Phosphatase

Kensei Nakamura, Yasuhiko Koga, Hiroyasu Sakai, Kazuaki Homma, and Mitsuo Ikebe
Circ. Res. 2007 101: 712-722. [Abstract] [Full Text] [PDF]

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