Myosin light chains dephosphorylation

Gong MC, Kinter MT, Somlyo AV, Somlyo AP. Arachidonic-acid and diacyl-glycerol release associated with inhibition of myosin light-chain dephosphorylation in rabbit smooth-muscle. J Physiol (Lond) 1995 486 113-122. 

Wu X, Haystead TAJ, Nakamoto RK, Somlyo AV, Somlyo AP. Acceleration of regulatory myosin light chain dephosphorylation and relaxation of smooth muscle by telokin and cyclic nucleotide-activated kinase. J Biol Chem 273 11362-11369... 

In the presence of calcium, the primary contractile protein, myosin, is phosphorylated by the myosin light-chain kinase initiating the subsequent actin-activation of the myosin adenosine triphosphate activity and resulting in muscle contraction. Removal of calcium inactivates the kinase and allows the myosin light chain to dephosphorylate myosin which results in muscle relaxation. Therefore the general biochemical mechanism for the muscle contractile process is dependent on the avaUabUity of a sufficient intraceUular calcium concentration. 

Ca2+ entry, Ca2+-uptake into the SR by SERCA, Ca2+ extrusion from the cell and dephosphorylation of the myosin light chains. The t ype 1 phosphatase, myosin light chain phosphatase (MLCP) dephosphorylates myosin. As with MLCK its activity is physiologically regulated, e.g. its activity is decreased following phosphorylation via Rho associated kinase (Somlyo Somlyo 2000). In the uterus we have found a small but significant reduction of force, but not Ca2+ when Rho-associated kinase is inhibited (Kupittayanant et al 2001b). 

NO released by GTN activates soluble, cytosolic form of guanylyl cyclase in vascular smooth muscles by interacting with haem group in the enzyme. This converts GTP to cGMP. cGMP dephosphorylates myosin light chain kinase and prevent myosin interaction with actin leading to relaxation. 

Relaxation follows the drop in cytosolic calcium below the activation threshold, which initiates release of calcium from calmodulin, whereupon calmodulin dissociates from the kinase catalytic subunit. This results in loss of myosin light chain kinase activity. Under these conditions, the dephosphorylation of myosin light chains will be the predominant reaction. Consequently, actin and myosin will no longer interact and the muscle relaxes. 

At a high concentration of calcium ion, calcium binds to calmodulin. In turn, calmodulin binds to and activates a protein kinase that phosphorylates myosin light chains. At low calcium concentration, the light chains are dephosphorylated by a calcium-independent phosphatase. 

The mechanism of action of nitrates involves activation of the nitric oxide (NO) pathway. The formation of NO in endothelial cells can be triggered by ACh, bradykinin, histamine, and serotonin. NO activates guanylyl cyclase to form cGMP, which effects a relaxation of vascular smooth muscle. Vasodilation occurs because cGMP promotes the dephosphorylation of myosin light-chain phosphate, preventing its interaction with actin. These mechanisms are summarized in Figure III-5-1. 

Nitrates increase NO concentrations. Increased NO activates guanylyl cyclase this increases cGMP levels, which dephosphorylates myosin light chains, decreasing their association with actin and thereby promoting smooth muscle relaxation. These mechanisms are summarized in Figure 111-5-1. 

Dephosphorylation of LC20 by myosin light chain phosphatase (MLCP) is described in Chapter 10, this volume. For dephosphorylation of distinct sites of LC20, we refer to Erdodi et al. (1989) and Barany et al. 

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