Signal transduction calmodulin

Small ubiquitous calcium-binding protein. Calmodulin binds and regulates the activity of many protein targets involved in cellular signal transduction pathways mediated by calcium. Calmodulin is ranked among the most conserved proteins and plays a key role in many cellular processes. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

Fig. 12. Tentative model of the signal transduction chain that links the perception of pectic fragments to defense responses in carrot cells. Abbreviations apy, heterotrimeric G protein CaM, calmodulin 4CL, 4-coumarate-CoA ligase CTX, cholera toxin FC, fusicoccine GDP-P-S and GTP-y-S, guanosine 5 -0-(2-thiodiphosphate) and guanosine 5 -0-(3-thiotriphosphate) IP3, 1,4,5-inositol trisphosphate PAL, phenylalanine ammonia-lyase PLC, phospholipase C PR, pathogenesis related PTX, pertussis toxin Rc, receptor SP, staurosporine. Activation and inhibition are symbolized by + and -respectively.

This linear scheme of signal transduction (Fig. 12) from hypothetical membrane receptors to [Ca " ] and IP3 increases, calcium-calmodulin interaction, kinases activation and gene transcription is clearly an oversimplification of the reality several receptors must exist that are connected to different transduction cascades that activate a series of defense genes. Cross-talking between the pathways further complicates the picture. However, this represents a starting model on which to elaborate more refined hypotheses. 

FIGURE 8.11 Multiple signal-transduction pathways initiated by calmodulin. Calmodulin bound to Ca2+ interacts and activates many enzymes, opening up a wide range of possible cellular responses. Abbreviations MAP-2, microtubule-associated protein 2 NO, nitric oxide Tau, tubulin assembly unit. 

Fig. 5 Proposed signal transduction mechanisms that stimulate the pheromone biosynthetic pathway in Helicoverpa zea and Bombyx mori. It is proposed that PBAN binds to a G protein-coupled receptor present in the cell membrane that upon PBAN binding will induce a receptor-activated calcium channel to open causing an influx of extracellular calcium. This calcium binds to calmodulin and in the case of B. mori will directly stimulate a phosphatase that will dephosphorylate and activate a reductase in the biosynthetic pathway. In H. zea the calcium-calmodulin will activate adenylate cyclase to produce cAMP that will then act through kinases and/or phosphatases to stimulate acetyl-CoA carboxylase in the biosynthetic pathway...

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]. 

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca + via activation of the inositol tris-phosphate (IP3) pathway. In concert with the protein calmodulin, Ca + can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction via the latter, P2-receptors mediate vasodilation, particularly in skeletal muscle - an effect that has little therapeutic use. 

Members of the protein kinase C family promote signal transduction by catalyzing ATP-dependent protein phosphorylation [general EC number 2.7.1.37] in response to various signals that promote lipid hydrolysis. The primary activator is diacylglycerol. See also Cal-cium/Calmodulin-Dependent Protein Kinase... 

The Ca Vcalmoduhn complex is a signal molecule that is involved in many signal transduction pathways. Ca Vcalmoduhn is involved in regulation of proliferation, mitosis, and in neuronal signal transduction. Different calmodulin subtypes are known which regulate different target proteins. 

The best characterized substrate of Ca Vcalmodulin is the Ca /calmodulin-depen-dent protein kinase (CaM kinase). CaM kinase has an important function in neuronal signal transduction. The mechanism of Ca Vcalmodulin activation of CaM kinase is described in more detail in Section 7.4, together with regulation of protein kinases. Another substrate of Ca Vcalmodulin is myosin light chain kinase (MLCK), involved in contraction of smooth musculature. 

A protein kinase or protein phosphatase may be regulated by different signal transduction pathways. Thus, different external stimuli may influence the phosphorylation status of a protein. This differential stimulation may be mediated by the subunits of the enzyme, for example. For phosphorylase kinase, a Ca signal is registered by the Ca T calmodulin subunit whereas a cAMP protein kinase A signal is picked up in the form of a phosphorylation of the a and P subunits. Which of the signals comes into play depends on the current metabolic situation. 

In general, the NOS isoforms can be grouped into two classes as determined by their expression in cells. Certain NOS isoforms, termed constitutive, appear to be expressed at a fairly constant level in their host cells. However, these isoforms are inactive in their native state and require that the Ca -binding protein calmodulin associate with them in order to generate NO (Schmidt et al., 1991 Busse and Mulsch, 1990 Bredt and Snyder, 1994). Thus NO production by constitutive NOS isoforms is often linked to Ca +-mediated signal transduction cascades that involve soluble guanylate cyclase, which is a hemeprotein that is activated by NO (Arnold et al., 1977). 

Furthermore, the LPS signal transduction involves the activation of G proteins, of phospholipases C and D, the formation of diacyl-glycerol (DG) and inositol triphosphate (IP3). DG mediates the stimulation of protein kinase C (PKC) and IP3 induces an increase of cytosolic Ca++ The LPS signaling pathway also involves tyrosine kinases, constitutive nitric oxide (NO) synthase (cNOS), cGMP-dependent protein kinase, Ca channels, calmodulin and calmodulin kinase [27,28], as well as the MAP kinases [29] ERK1, ERK2 and p38 [23], The intracellular events in response to LPS are due to lipid A because they are inhibited by polymyxin B which is known to bind lipid A [27] and they are reproduced by lipids A [30,31]. 

L. J. van Eldik and D. M. Watterson, Calmodulin and Signal Transduction , Academic Press, New York, 1998. 

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