Calcium-calmodulin complex

Calcium-dependent regulation involves the calcium-calmodulin complex that activates smooth muscle MLCK, a monomer of approximately 135 kDa. Dephosphorylation is initiated by MLCP. MLCP is a complex of three proteins a 110-130 kDa myosin phosphatase targeting and regulatory subunit (MYPT1), a 37 kDa catalytic subunit (PP-1C) and a 20 kDa subunit of unknown function. In most cases, calcium-independent regulation of smooth muscle tone is achieved by inhibition of MLCP activity at constant calcium level inducing an increase in phospho-rMLC and contraction (Fig. 1). 

Ral has attracted much interest in recent years, not least because it was demonstrated to mediate part of Ras function as described above. In contrast to Rap, which rather inhibits Ras signaling, Ral is part of one of the essential Ras-activated pathways. Moreover, it has proved to be acting in parallel with the Raf pathway in cell transformation induced by oncogenic Ras [37, 77]. The case of Ral demonstrates the complexity - and the incomplete knowledge and understanding - of signal transduction. Ral can also be activated by Rap mediated by Rif [103] and, alternatively, by binding of a calcium/calmodulin complex to the Ral C-terminus which obviously does not affect the nucleotide state of Ral [111]. 

Mitochondrial dysfunction is believed to play a vital role in the pathogenesis of acute renal failure. In the face of inadequate production of mitochondrial ATP, sodium and calcium efflux from the cell, which requires ATP, is curtailed. This leads to the swelling of the cell and activation of the calcium-calmodulin complex. The latter may activate phospholipases, which in turn can damage the cell membrane and cause swelling of the cell, leading to its death. The cell debris serves as a substrate for tubular obstruction and supports the maintenance phase of acute renal failure. Complications of casts solidifying in the tubular lumen can be avoided by early measures to prevent cell death. 

Another theory is that calcium may not directly activate an enzyme to trigger secretion, but rather may first interact with a cytoplasmic protein, calmodulin. The calcium-calmodulin complex may then cause enzyme activation. The enzyme phosphodiesterase is known to be activated by such a calcium-calmodulin complex (26). 

Calmodulin is a major intracellular calcium-binding protein which regulates a wide variety of calcium-dependent processes (Cheung 1982). The binding of calcium to calmodulin induces a conformational change in the protein to an active form. The calcium-calmodulin complex is then capable of regulating a host of other molecules such as phosphodiesterase, adenylate kinase, protein kinases, and Ca-ATPase. Cadmium has been shown to... 

Although in in vivo circumstances an intracellular free calcium increase apparently acts as the primary modulator of contraction, it can be bypassed in highly permeabilized smooth muscle preparations where the active subunit of MLCK can be introduced to phosphorylate myosin and induce contraction. The MLCK catalyzed phosphorylation of serine-19 is seen as the necessary event in the activation of smooth muscle myosin to form crossbridges. Thus, the rising phase of force during an isometric smooth muscle contraction follows an increase in the degree of phosphorylation of myosin, and that in turn follows the transient rise of (a) cytosolic free Ca, (b) Ca-calmodulin complexes, and (c) the active form of MLCK. The regulation of the intracellular calcium is discussed below. The dynam-... 

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. 

In addition to the displacement of caldesmon, smooth muscle cell contraction requires kinase-induced phosphorylation of myosin. Smooth muscle has a unique type of myosin filament called p-light chains which are the target (substrate) for MLCK, but MLCK is only active when complexed with CaCM. Myosin light chain phosphatase reverses the PKA-mediated process and when cytosolic calcium ion concentration falls, CDM is released from CaCM and re-associates with the actin. The central role of calcium-calmodulin in smooth muscle contraction is shown in Figure 7.4. 

Dolmetsch R, Pajvani U, Fife K, Spotts JM, Greenberg ME (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294 333-339... 

Kahl, C. R. and Means, A. R., 2004, Regulation of cyclin Dl/Cdk4 complexes by calcium/calmodulin-dependent protein kinase I, J Biol Chem, 279, pp 15411-9. 

Currie, S., Loughrey, C. M., Craig, M. A., and Smith, G. L. (2004). Calcium/Calmodulin-Dependent Protein Kinase Ildelta Associates with the Ryanodine Receptor Complex and Regulates Channel Function in Rabbit Heart. Biochem J 377(Pt 2) 357-66. 

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