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Functional Properties of Muscle
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Ca2+ bind to the protein calmodulin (Section 6.3.1), which activates the enzyme myosin light chain kinase (MLCK). This enzyme phosphorylates the myosin light chain in the myosin head, in the presence of ATP. Only when the myosin head is phosphorylated can it combine with actin to form cross bridges and initiate cross-bridge recycling through ATP splitting. To relax the muscle, the myosin is dephosphorylated by the enzyme myosin light chain phosphatase, which is continuously active in smooth muscle. However, when the concentration of Ca2+ rises, the rate of phosphorylation exceeds that of dephosphorylation and cross-bridge recycling occurs. The converse applies when the concentration of Ca2+ falls.
Effect of Mucosal Inflammation on Colonic Smooth Muscle Contraction
Published in William J. Snape, Stephen M. Collins, Effects of Immune Cells and Inflammation on Smooth Muscle and Enteric Nerves, 2020
Yining Xie, William T. Gerthoffer, S. Narasimha Reddy, Viktor E. Eysselein, Fabio Cominelli, William J. Snape
The activity of phosphatase was indirectly examined in skinned muscle using ATPγS which is an effective substrate for myosin light chain kinase, but a poor substrate for myosin light chain phosphatase21. All the solutions were prepared as above. After the relaxing solution, addition of pCa 6.5 contracting solution confirmed that the tissue was skinned and viable. When the isometric force reached the maximum for two minutes, pCa 8.0 relaxing solution was superfused until the baseline in the tension recording returned to the basal level. Thirty ml of relaxing solution, which did not contain ATP or ATP generating system, was superfused for 15 minutes to wash Na2ATP from the chamber. Instead of Na2ATP, 5.0 mM ATPγS was added to the pCa 6.5 contracting solution in the absence of ATP-regenerating system. After the contraction reached the maximum for about two minutes, relaxing solution without ATP and ATP-regenerating system was perfused until a stable baseline appeared. The pCa 8.0 contracting solution containing Na2ATP and ATP-regenerating system was perfused and kept in the chamber until the muscle strips contracted and then spontaneously relaxed to a stable line on the chart paper.
Vascular smooth muscle: excitation, contraction and relaxation
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
The phosphate group can be removed by the enzyme myosin light chain phosphatase (MLCP) (Figure 12.7). When intracellular Ca2+ concentration falls, MLCK activity declines and the competing myosin phosphatase dominates, dephosphorylating the myosin. Since dephosphorylated myosin cannot form new crossbridges, the phosphatase in effect turns off the myosin motor. As existing crossbridges detach, new ones cannot form, so the myocytes relax, leading to vasodilatation. Increased myosin phosphatase activation may explain cases of vascular relaxation with little fall in cytosolic Ca2+ concentration, for example hypoxic vasodilatation (Figure 13.5). Phosphatase inhibition is promoted by the activation of RhoA kinase (see Figure 12.7).
Molecular aspects of the altered Angiotensin II signaling in Gitelman’s syndrome
Published in Expert Opinion on Orphan Drugs, 2022
Verdiana Ravarotto, Giovanni Bertoldi, Lucia Federica Stefanelli, Laura Gobbi, Lorenzo A. Calò
In summary, the increased expression of RGS-2 in GS determines the reduced expression of the Ga subunit which is reflected in reduced PLCβ activity and subsequently reduced IP3 and diacylglycerol (DAG). The former influence Ca2+ release, which is less prone to form the complex Ca2+-calmodulin (Ca2+/CaM), the latter reduces PKC activity with consequent increased eNOS expression and reduced vascular tone [42,54,56]. Altogether these intracellular pathways influence muscle contraction and peripheral resistance by reducing the phosphorylation of the regulatory chain of myosin II. The activation of the G-protein RhoA and its effector Rho kinase (ROCK) regulates, in fact, the phosphorylation state of the myosin phosphatase target protein subunit-1 (MYPT-1) which is the regulatory subunit of the myosin light chain phosphatase (MLCP). In its active state, MLCP de-phosphorylates myosin light chain (MLC) promoting the relaxation process of the vascular smooth muscle. The ROCK-induced MYPT-1 phosphorylation has an inhibitory effect on MLCP which is associated with increased phosphorylation of the MLC that promotes actin–myosin interaction and muscle contraction [57]. MLC phosphorylation is therefore fine-tuned by the relationship between the myosin light chain kinase (MLCK) and MLCP activities [58].
Current insights in the complexities underlying drug-induced cholestasis
Published in Critical Reviews in Toxicology, 2019
Neel Deferm, Tom De Vocht, Bing Qi, Pieter Van Brantegem, Eva Gijbels, Mathieu Vinken, Peter de Witte, Thomas Bouillon, Pieter Annaert
Unidirectional flow of bile towards bile ducts is facilitated by spontaneous rhythmic contractions of the biliary lumen. These contractions, also termed bile canalicular dynamics, are controlled by a complex network of actin and myosin microfilaments as well as other contractile proteins (Oshio and Phillips 1981). Myosin ATPase activity, which catalyzes recurrent interactions of actin with myosin via hydrolysis of ATP. The latter is an important step in the development of acto-myosin-based contractile forces (Burbank et al. 2016). These contractions are preceded by activation of the RhoA/Rho-kinase (ROCK) pathway, which results in inhibition of myosin light chain phosphatase (MLCP) and subsequently enhanced phosphorylation of myosin light chains (MLCs) (Figure 4) (Mills et al. 1998). Contractile activity is equally stimulated through phosphorylation of MLCs by Ca2+/calmodulin (CaM)-dependent myosin light-chain kinase (MLCK) (Isotani et al. 2004). RhoA/ROCK is known to regulate intrahepatic vascular tone in human cirrhotic liver and in BDL rats, whilst also playing a crucial role in the assembly of tight junctions (Zhou et al. 2006; González-Mariscal et al. 2008).
Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ramon Guerra de Oliveira, Fabiana Sélos Guerra, Cláudia dos Santos Mermelstein, Patrícia Dias Fernandes, Isadora Tairinne de Sena Bastos, Fanny Nascimento Costa, Regina Cely Rodrigues Barroso, Fabio Furlan Ferreira, Carlos Alberto Manssour Fraga
Activation of ROCKs by GTPases, mainly Rho, or by alternative pathways involving caspases or lipid mediators leads to the phosphorylation of several molecular targets. One of the main substrates of ROCK-mediated phosphorylation is MLC (myosin light chain), since the activation of these proteins was initially reported to be associated with the formation of stress fibres and changes in the cytoskeleton4,7. In this manner, ROCKs directly phosphorylate myosin light chain, promoting the actin-myosin interaction. In addition, ROCKs phosphorylate and inactivate MLCP (myosin light chain phosphatase), indirectly regulating the amount of phosphorylated myosin4,8.