Calmodulin activation

Once the intracellular Ca " concentration begins to rise, calmodulin-calcium binding also rises and MLCK, which is dependent on calmodulin activation, rises in turn. The next step in this cascade is the phosphorylation of myosin. Finally, the phosphorylation of myosin results in the activation of the crossbridges and the accompanying transduction of ATP energy into mechanical work. Despite its differences in regulation, smooth muscle behaves mechanically much like other muscles. 

Calmodulin-activated or deactivated enzymes and other proteins... 

Secondary signals Glucose 6-phosphate activates synthesis. Ca2+-Calmodulin activates degradation by activating phosphorylase kinase. 

Calmodulins Activate a variety of enzymes and pumps — see text (362-364)... 

Calmodulin, a calcium binding protein, is involved in Ca2+-dependent regulation of several synaptic functions of the brain synthesis, uptake and release of neurotransmitters, protein phosphorylation and Ca+2 transport. It reacts with TET, TMT and TBT which then inactivates enzymes like Ca+2-ATPase and phosphodiesterase. In vitro studies indicated TBT was greater at inhibiting calmodulin activity than TET and TMT, whereas in vivo the order was TET > TMT > TBT. This may be due to the greater detoxification of TBT (66%) in the liver before moving to other organs30,31. 

In addition to the regulatory mechanisms discussed above, an interesting form of Ca2+-dependent inactivation of NMDA receptors is brought about by calmodulin. Activated by Ca2+ entry, calmodulin interacts with the C-terminal domain of the NR1 subunit (Fig 15-4B) this interaction causes inactivation of the receptor manifested... 

The cAMP and Ca2+ pathways also interact at the level of protein kinases and protein phosphatases. This is illustrated by inhibitor-1 and DARPP-32, which are phosphorylated and activated by PKA and then inhibit PP1, which can dephosphorylate numerous substrates for Ca2+-dependent protein kinases. Another example is the physical association between PKA and PP2B (a Ca2+/ calmodulin-activated enzyme) via the AKAP-anchoring proteins. 

Because of its ability to bind CaM, tamoxifen can increase cyclic AMP surges by inhibiting cyclic AMP hydrolysis by the Ca2+-calmodulin-dependent cyclic nucleotide phosphodiesterase (Fanidi et al. 1989 Rowlands et al. 1990). In bovine brain preparations, tamoxifen appears to act as a competitive inhibitor of calmodulin-activated phosphodiesterase with an IC50 of 2 p,M, similar to the value reported for trifluoperazine under the same experimental conditions (Lam 1984). 

As explained, the immimomodulation signal starts with binding the antigen on T-cell receptor, which ultimately results in Ca2+ release. Ca2+ induces calmodulin activation, which in turn activates calcineurin, a Ca2+-dependent phosphatase. This event leads to translocation of the cytoplasmic component of the transcription factor, which is required for IL-2 gene expression and T-cell activation. 

In addition to these kinases, there are undoubtedly others in neutrophils, including Ca2+/calmodulin-activated kinases, which regulate function. Furthermore, there are a variety of phosphatases that can reverse the effects... 

Desaiah D, Chetty CS, Prasada Rao KS. 1985. Chlordecone inhibition of calmodulin activated calcium ATPase in rat brain synaptosomes. J Toxicol Environ Health 16 189-195. 

Desaiah D, Pentyala SN, Tottman CH, et al. 1991. Combined effects of carbon tetrachloride and chlordecone on calmodulin activity in gerbil brain. J Toxicol Environ Health 34(2) 219-228. 

Kodavanti PR S, Mehrotra BD, Cherry SC, et al. 1989c. Inhibition of calmodulin-activated adenylate cyclase in rat brain by selected insecticides. Neurotoxicology 10(2) 219-228. 

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... 

Calmodulin binds to and activates neuronal NOS (Bredt and Snyder, 1990 Schmidt et al., 1991), and also functions as a tightly bound prosthetic group to keep macrophage NOS in its active state (Cho et al., 1992). Work with the neuronal NOS has uncovered the basis for its calmodulin activation Calmodulin binding triggers electrons to transfer onto the NOS heme iron (Abu-Soud and Stuehr, 1993) (Fig. 10). Because this transfer is associated with initiation of... 

Toeroek, K. Cowley, D.J. Brandmeier, B.D. Howell, S. Aitken, A. Tren-tham, D.R. Inhibition of calmodulin-activated smooth-muscle myosin light-chain kinase by calmodulin-binding peptides and fluorescent (phosphodiesterase-activating) calmodulin derivatives. Biochemistry, 37, 6188-6198 (1998)... 

Yamaguchi, K. Hirata, M. Kuriyama, H. Calmodulin activates inositol... 

The release of Ca2+ in response to such second messengers is known to activate the phosphorylation of a range of cytosolic proteins by Ca2+-dependent protein kinases, for example in hepatocytes,417 adrenal cortex418 and other cells.419 Ca2+ inhibits cAMP-activated protein kinase in parathyroid glands.420 Phosphorylation of proteins produced in the pancreatic /8-cell in response to enhanced [Ca2+] may involve calmodulin, while the stimulus produced by glucose is potentiated by cAMP 421 A calmodulin-activated NAD kinase is present in the outer mitochondrial membrane of com.422... 

Hawley, S. A., Seibert, M. A., Goldstein, E. G., Edelman, A. M., Carling, D. and Hardie, D. G., 1995, 5 -AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms, J Biol Chem, 270, pp 27186-91. 

Table 18.1 Substrate (autocamtide-2) and calmodulin activation kinetics in recombinant CaMKII holoenzymes purified from Baculovirus-infected insect cells...

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.

Snedden, W.A., Arazi, T., Fromm, H. and Shelp, B.J. (1995) Calcium/calmodulin activation of soybean glutamate decarboxylase. Plant Physiol, 108, 543-9. 

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