Ca2+-calmodulin CAM-dependent

Fig. 11.1 Activation of MAPK pathway by Angll and ET-1 in VSMC. Stimulation of Angll and ET-1 receptors through Gq/n activation enhances the activity of PLCp. Activated PLC 3 converts PIP2 to IP3 and diacylglycerol (DAG). IP3 elevates the concentration of intracellular calcium and DAG activates PKC. PKC and/or Ca2+/calmodulin (CaM)-dependent protein kinases (CaMK) activate nonreceptor (NR) and/or receptor (R) protein tyrosine kinases. Activation of these components signals the stimulation of Ras/Raf/MEK/ERKl/2 and p70 s6k. ERK1/2 and p70 s6k are translocated to nucleus and regulate nuclear events by activating transcription factors through phosphorylation.

FIGURE 21-6 Schematic illustration of the overall structure and regulatory sites of eleven different phosphodiesterase subtypes. The catalytic domain of the phosphodiesterases are relatively conserved, and the preferred substrate(s) for each type is shown. The regulatory domains are more variable and contain the sites for binding of Ca2+/calmodulin (CaM) and cGMP, as well as GAF and PAS domains. The regulatory domains also contain sites of phosphorylation by cAMP-dependent protein kinase (PKA). 

Sustained cytosolic Ca2+ overload usually results in a different route leading to cell death. It mainly relies on the activation of the calcium/calmodulin (CaM)-dependent phosphatase, calcineurin. Calcineurin-catalyzed dephosphorylation promotes apoptosis by regulating the activity of a number of downstream targets, including the pro-apoptotic Bcl-2 family member, Bad (Wang, et al., 1999), and transcription factors of the NFAT (nuclear factor of activated T cells) family (Rao, et al., 1997). There are also other Ca2+-dependent enzymes contributing to the apoptotic events, and they include several DNA-degrading endonucleases (Robertson, et al., 2000) and Ca2+-activated cystein proteases of the calpain family essential for the enzymatic activation of the crucial pro-apoptotic effectors (Altznauer, et al., 2004). 

Fig. 2. A schematic representation of some of the mechanisms by which Car fluxes across the plasma membrane are regulated. In the plasma membrane (the striped area) there are both influx (=>) and energy-dependent ( ) efflux pathways. Two mechanisms by which Ca2+ influx can be increased are via the actions of the intracellular messengers inositol 1,3,4,5-tetrakisphosphate, and cAMP generated via activation of specific classes of surface receptors (R, and R2) linked to specific N proteins which activate either phosphatidylinositol 4,5-bisphosphate (PIP,) hydrolysis or adenylate cyclase (AC). Additionally, influx can be increased either by a direct receptor-coupled event or by a membrane depolarization (not shown). A rise in the Ca2+ concentration in the domain just beneath the plasma membrane, [Ca2+Isin, can lead to an activation of the Ca2+ pump either via a direct calmodulin (CaM)-dependent mechanism, or indirectly via the activation of protein kinase C (CK). Additionally, in some cells, an increase in cGMP concentration also increases Ca2+ efflux (not shown), and in still others cAMP may stimulate Ca2 efflux.

PDE1 is phosphorylated by Ca27calmodulin-dependent protein kinase II (CaM-kinase II), which results in decreased affinity of this enzyme for Ca2+/calmodulin and an increase in the concentration of Ca2+ needed for its activation. PDE1 is also phosphorylated by protein kinase A, which likewise decreases its binding to Ca27calmodulin. 

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). 

G protein-coupled receptor kinases (GRKs) 441 scaffold proteins 441 inhibitory G protein (GO 441 calmodulin (CaM) 444 Ca2+/calmodulin-dependent protein kinases (CaM kinases I IV)) 444 two-component signaling systems 452 receptor His kinase 452 response regulator 452 receptorlike kinase (RLK) 455... 

Meanwhile, the polar IP3 moiety binds to intracellular receptors on the endoplasmic reticulum, resulting in the liberation of calcium into the cytosol. The calcium binds to calmodulin, which then activates another group of protein kinases (the Ca2+/CaM-dependent protein kinases). Hormonal stimulation can be short-lived because IP3 and DG are rapidly degraded to inactive forms that are ultimately recycled to PIP2 Ca2+ is pumped back into the endoplasmic reticulum, where it is sequestered. 

Calmodulin (CaM), a Ca2+-binding protein, binds directly to the NR1 subunit of the NMDA receptor in a Ca2+-dependent manner. CaM binding occurs at two distinct sites in the COOH -terminal region of NR1 molecule. One CaM binding site is contained within the spliced Cl exon cassette, whereas the other is located in a region common to all NR1 splice variants (Ehlers et al., 1996). Collective evidence suggests that NMDA receptor function can be modulated by CaM binding to the NR1 subunit and this process may be related to activity-dependent feedback inhibition and Ca2+-dependent inactivation of NMDA receptors. 

Hanissian, S. H., Frangakis, M., Bland, M. M., Jawahar, S. and Chatila, T. A., 1993, Expression of a Ca2- -/calmodulin-dependent protein kinase, CaM kinase-Gr, in human T lymphocytes. Regulation of kinase activity by T cell receptor signaling, J Biol Chem, 268, pp 20055—63. 

Park, I. K. and Soderling, T. R., 1995, Activation of Ca2+/calmodulin-dependent protein kinase (CaM-kinase) IV by CaM-kinase kinase in Jurkat T lymphocytes, J Biol Chem, 270, pp 30464-9. 

Sakagami, H., Umemiya, M., Kobayashi, T., Saito, S. and Kondo, H., 1999, Immunological evidence that the beta isoform of Ca2 +/calmodulin-dependent protein kinase TV is a cerebellar granule cell-specific product of the CaM kinase TV gene, Eur J Neurosci, 11, pp 2531-6. 

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