Muscle contraction myosin light chain kinase

Ca2+ regulation of smooth muscle contraction. Myosin light-chain kinase (MLCK) phosphorylates myosin and causes contraction, in response to calcium, as shown in this signaling pathway. 

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. 

Smooth muscle contractions are subject to the actions of hormones and related agents. As shown in Figure 17.32, binding of the hormone epinephrine to smooth muscle receptors activates an intracellular adenylyl cyclase reaction that produces cyclic AMP (cAMP). The cAMP serves to activate a protein kinase that phosphorylates the myosin light chain kinase. The phosphorylated MLCK has a lower affinity for the Ca -calmodulin complex and thus is physiologically inactive. Reversal of this inactivation occurs via myosin light chain kinase phosphatase. 

Smooth muscle myosin contains two myosin light chains. Phosphorylation of the regulatory light chain by myosin light chain kinase is a mandatory step to induce contraction. 

The calcium mediated contraction of smooth muscle, which unlike striated muscle does not contain troponin, is quite different and requires a particular calcium-binding protein called calmodulin. Calmodulin (CM) is a widely distributed regulatory protein able to bind, with high affinity, four Ca2+ per protein molecule. The calcium—calmodulin (CaCM) complex associates with, and activates, regulatory proteins, usually enzymes, in many different cell types in smooth muscle the target regulatory proteins are caldesmon (CDM) and the enzyme myosin light chain kinase (MLCK). As described below, CaCM impacts on both actin and myosin filaments. 

These messengers also play a role in regulating contraction of myometrium, which consists of smooth muscle fibres. Contraction is controlled by increases in the concentration of cytosolic Ca ions. Prostaglandins activate Ca ion channels in the plasma membrane of the fibres oxytocin activates release of Ca from intracellular stores. The increase in concentration of Ca ions leads to activation of myosin light-chain kinase which leads to crossbridge cycling and contraction (as described in Chapter 22 Figure 22.12). 

Many of the biochemical and molecular events that are responsible for uterine smooth muscle contraction are the same as those that control other smooth muscle tissues (Fig. 62.1). Once uterine smooth muscle sensitivity has been augmented, actin and myosin must interact for contraction to occur. This interaction depends on the phosphorylation of the contractile proteins by the enzyme myosin light chain kinase (MLCK). This enzyme requires Ca++ and is active only when associated with calmodulin. Activation of the entire muscle contraction... 

Q6 Salbutamol is a selective beta-2-adrenoceptor (/ -adrenoceptor) agonist which is effective in relieving mild to moderate bronchoconstriction. Inhalation of salbutamol induces bronchodilation by acting on /J2-receptors on bronchial smooth muscle this lasts for approximately three to five hours. It also inhibits mediator release and improves the clearance of mucus from the lung. Stimulation of the /02-receptor increases the cellular concentration of cyclic adenosine monophosphate cAMP and activates a protein kinase. This kinase in turn inactivates myosin-light-chain kinase, an enzyme necessary for contraction in smooth muscle, and so relaxes bronchial smooth muscle. 

Figure 6.10. Calcium-dependent signalling by adrenergic receptors. a p-Adrenergic receptors activate adenylate cyclase. cAMP activates protein kinase A (PKA). In heart muscle, PKA phospho-rylates several Ca transporters and charmels, so that the amount of Ca available for contraction is increased. PL Phospholam-ban SERCA SR/ER Ca transporter, b In smooth muscle, myosin activation in works by way of phosphorylation, which is performed by myosin light chain kinase (MLCK). Inactivation is accomplished by myosin light chain phosphatase (MLCP). c aj-Adrenergic receptors stimulate phospholipase C, which releases inositoltriphosphate (IP3). IP3 binds to a cognate ligand-gated Ca chaimel in the ER and releases Ca, which with calmodulin activates MLCK.

In smooth muscle, contraction is controlled by the phosphorylation state of the myosin regulatory light chain. The extent of this phosphorylation will depend on the regulatory states of both myosin light chain kinase (MLCK) and of... 

In skeletal muscle, disinhibition of actin is necessary for contraction to occur, and control of contraction is said to be actin-linked. In smooth muscle, phosphorylation of myosin light chains (MLCs) is required for contraction. Several mechanisms alter MLC phosphorylation, and so in smooth muscle, control of contraction is primarily myosin-linked. Three control proteins have been identified in smooth muscle myosin light chain kinase (MLCK) caldesmon (CaD) and calponin (CaP). Figure 21-14... 

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