Actin action mechanisms

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. 

More than 50 proteins have been discovered in the cytosol of nonmuscle cells that bind to actin and affect the assembly and disassembly of actin filaments or the cross-linking of actin filaments with each other, with other filamentous components of the cytoskeleton, or with the plasma membrane. Collectively, these are known as actin-binding proteins (ABPs). Their mechanisms of actions are complex and are subject to regulation by specific binding affinities to actin and other molecules, cooperation or competition with other ABPs, local changes in the concentrations of ions in the cytosol, and physical forces (Way and Weeds, 1990). Classifications of ABPs have been proposed that are based on their site of binding to actin and on their molecular structure and function (Pollard and Cooper, 1986 Herrmann, 1989 Pollard et al., 1994). These include the following ... 

The cellular/molecular mechanism of action for these cyclic peptide toxins is now an area of active research in several laboratories. These peptides cause striking ultrastructural changes in isolated hepatocytes (95) including a decrease in the polymerization of actin. This effect on the cells cytoskeletal system continues to be investigated and recent work indirectly supports the idea that these toxins interact with the cells cytoskeletal system (86,96). Why there is a specificity of these toxins for liver cells is not clear although it has been suggested that the bile uptake system may be at least partly responsible for penetration of the toxin into the cell (92). 

The marine macrolides latrunculin A and the less potent variation latrunculin B (5-25 pg/mL, 60 minutes) bind to actin and disrupt the cytoskeleton at low concentrations (90,91). Their mechanism of action includes binding to and sequestering actin monomers, resulting in filament depolymerization (89). 

Allingham JS, Klenchin VA, Rayment I, Actin-targeting natural products Structures, properties and mechanisms of action. Cell Mol Life Sci 63 2119-2134, 2006. 

Imiquimod (Aldara) is an immunomodulator approved for the treatment of external genital and perianal warts in adults, actinic keratoses on the face and scalp, and biopsy-proven primary basal cell carcinomas on the trunk, neck, and extremities. The mechanism of its action is thought to be related to imiquimod s ability to stimulate peripheral mononuclear cells to release interferon- and to stimulate macrophages to produce interleukins-1, -6, and -8, and tumor necrosis factor- (TNF-k). 

A topical 3% gel formulation of the nonsteroidal anti-inflammatory drug diclofenac (Solaraze) has shown moderate effectiveness in the treatment of actinic keratoses. The mechanism of action is unknown. As with other NSAIDs, anaphylactoid reactions may occur with diclofenac, and it should be given with caution to patients with known aspirin hypersensitivity (see Chapter 36). 

Brown, S.S., and J.A. Spudich. 1981. Mechanism of action of cytochalasin Evidence that it binds to actin filament ends. J Cell Biol 88 487. 

FIGURE 13-3 Possible mechanism of action of dantrolene sodium (DantriurrQ. Dantrolene blocks channels in the sarcoplasmic reticulum, thus interfering with calcium release onto the contractile [actin, myosin] filaments. Muscle contraction is reduced because less calcium is available to initiate cross-bridge formation between actin and myosin filaments. 

The present volume covers Muscle and Molecular Motors . The first few chapters describe the ultrastructures of striated muscles and of various muscle filaments (myosin, actin, titin), they discuss the regulation of muscle contractile activity, and they explore the mechanism of force production and movement. The book then sets out to survey other kinds of motor systems microtubules and their interactions with both microtubule associated proteins (MAPs) and the motor proteins kinesin and dynein, the major sperm protein in nematodes, the rotary ATPases driven by or driving proton gradients, and the action of motor enzymes, polymerases, on nucleic acids. The aim throughout is to explore different molecular mechanisms of motor action in order to identify common themes. 

Simulation of glucose transport and glucose transporter translocation from intracellular stores to the plasma membrane in muscle cells by vanadate and peroxovan-adate involve a mechanism independent of PI-3K and protein kinase C systems utilized for stimulation of these processes by insulin. The transport of GLUT4 to the plasma membrane in muscle cells growing in culture after stimulation by vanadate, peroxovanadate, or insulin all require an intact actin network [138], Sometimes, the insulin-like action of vanadium is accompanied by overall stimulation of actual metabolic pathways. One example of this is the stimulation of the pentose phosphate pathway observed when vanadate promotes the incorporation of glucose into lipids, an antilipogenic effect [139],... 

The physiology of muscle action and how it is fired are discussed in this book in connection with the mechanism of action of the nervous system (14.4). All that will be said here is that when then above reaction (14.13) run spontaneously in reverse, a supply of energy and protons activates the myofibrils, which are composed of thin filaments made up of the protein actin and thick filaments of the protein myosin. It is the relative movement of these two filaments that is the essence of muscle action. 

An enhancement of ATPase action comes through the phosphorylation of myosin light chains (MW 18,000). The phosphorylation is achieved because the high cellular [Ca2+] activates myosin kinase, an enzyme that contains calmodulin, a Ca2+-binding subunit. Phosphorylation of myosin is absolutely required for smooth muscle contraction, though not for the contraction of skeletal or cardiac muscle, because smooth muscle has no troponin. Thus, whereas contraction and relaxation in skeletal and cardiac muscle are achieved principally via the action of Ca2+ on troponin, in smooth muscle they must depend solely on the Ca2+-dependent phosphorylation of myosin. In skeletal and cardiac muscle, once the stimulus to the sarcolemma is removed, [Ca2+] in sarcoplasm drops rapidly back to 10 7 or 10 8 M via various Ca2+ pump mechanisms present in the sarcoplasmic reticulum, and tropomyosin can once again interfere with the myosin-actin interaction. 

Muscle contraction is complex, requiring the action of many different myosin molecules. Studies of single myosin molecules moving relative to actin fdaments have been sources of deep insight into the mechanisms underlying muscle contraction and other complex processes. 

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