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Miscellaneous Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Beta-adrenergic tocolytic drugs bind to beta-adrenergic receptors on the outer myometrial cell membrane and activate adenylate cyclase, which catalyzes conversion of ATP to cAMP. Increased intracellular cAMP levels activate cAMPase-dependent protein kinase and decreases intracellular calcium concentration, reducing myometrial contractility (Caritis et al., 1989; Roberts, 1984). Phosphorylation of myosin light chain kinase, another pathway, inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain. Maternal metabolic abnormalities (gluconeogenesis, hypokalemia, and hyperglycemia), and cardiopulmonary complications (tachycardia, hypotension, arrhythmias, myocardial ischemia, pulmonary edema) are associated with beta-agonist tocolysis (Box 15.2). Apprehension, electrocardiogram (EKG/ECG) changes (S-T segment depression) and maternal death are associated with beta-adrenergic agonist tocolytic agents. Every beta-agonist is associated with an increased frequency of pulmonary edema, occurring among <5 percent of pregnant women who use these drugs (Boyle, 1995; McCombs, 1995).
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
Tension development and shortening of the smoothmuscle cell is due to the formation of cross-bridges of myosin with actin, associated with the hydrolysis of ATP. Phosphorylation of the serine residue at the C-terminal of the two 20 KD Tension development and shortening of the smoothmuscle cell is due to the formation of cross-bridges of myosin with actin, associated with the hydrolysis of ATP. Phosphorylation of the serine residue at the C-terminal of the two 20 KD light chains of myosin by myosin light chain kinase, which is initiated by an increased intracellular concentration of ionized Ca2+, is required for cross-bridge formation. When the intracellular concentration of ionized Ca2+ decreases, the myosin light chain phosphatase removes the phosphate from the light chains and terminates active cross-bridge formation10.
Simvastatin Attenuates Glucocorticoid-Induced Human Trabecular Meshwork Cell Dysfunction via YAP/TAZ Inactivation
Published in Current Eye Research, 2023
Hannah Yoo, Ayushi Singh, Haiyan Li, Ana N. Strat, Tyler Bagué, Preethi S. Ganapathy, Samuel Herberg
Myosin light chain is a master regulator of cell contractility when phosphorylated by Rho kinases via the generation of pulling forces from actomyosin filament contraction.69–71 Increased phospho-myosin light chain (p-MLC) is strongly associated with a pathologic hypercontractile TM cell phenotype akin to activated myofibroblasts.4,47,68 In contrast, a decrease in p-MLC has been shown to increase aqueous outflow facility in perfusion studies.72 Statin-mediated inhibition of the mevalonate pathway directly affects downstream Rho GTPase signaling;40 therefore, we hypothesized that simvastatin decreases glucocorticoid-induced pathologic p-MLC levels in HTM cells. Dexamethasone treatment significantly increased p-MLC intensity in HTM cells (∼4.2-fold) compared to controls; simvastatin alone had no effect on p-MLC levels (Figure 3(A,B)). Co-treatment with dexamethasone + simvastatin significantly decreased p-MLC intensity (∼0.8-fold) compared to dexamethasone-induced HTM cells, restoring control levels. The addition of mevalonate-5-phosphate significantly increased p-MLC intensity (∼4.3-fold) compared to dexamethasone + simvastatin, indistinguishable from dexamethasone-treated HTM cells. Different HTM cell strains significantly affected the results (p < 0.0001), showing significant interaction with the different treatments (p < 0.0001).
S1P in the development of atherosclerosis: roles of hemodynamic wall shear stress and endothelial permeability
Published in Tissue Barriers, 2021
Christina M Warboys, Peter D Weinberg
Exposure of endothelial cells to S1P results in rapid actin polymerization and dynamic reorganization of the actin cytoskeleton, forming a prominent cortical actin band29,33,36,37,41 that is essential for the barrier-enhancing effects of S1P.29 Several studies have also shown that Rac GTPase is rapidly activated in response to S1P29,38,39,41 and that this depends on the activation of PI3K and recruitment of Tiam1, a Rac1 guanine nucleotide exchange factor.37 Rac plays a critical role in mediating S1P-induced cytoskeletal remodeling via activation of p21-associated Ser/Thr kinase (PAK).29,41 PAK may act at several levels to promote the dynamic reorganization of the cytoskeleton into dense peripheral bands that strengthen barrier function. Myosin light chain (MLC) can be phosphorylated by PAK61 and indeed phosphorylated MLC has been shown to localize to peripheral bands in response to S1P.29,36 PAK also phosphorylates and activates LIM kinase (LIMK), which inhibits cofilin (an actin severing protein) thus preventing actin depolymerization and promoting the formation of actin filaments.62
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.