Calmodulin protein kinase

So far, it has been established from in vitro studies that the enzyme undergoes phosphorylation, a process that changes the conformation of the enzyme protein and leads to an increase in its activity. This involves Ca +/calmodulin-dependent protein kinase II and cAMP-dependent protein kinase which suggests a role for both intracellular Ca + and enzyme phosphorylation in the activation of tryptophan hydroxylase. Indeed, enzyme purified from brain tissue innervated by rostrally projecting 5-HT neurons, that have been stimulated previously in vivo, has a higher activity than that derived from unstimulated tissue but this increase rests on the presence of Ca + in the incubation medium. Also, when incubated under conditions which are appropriate for phosphorylation, the of tryptophan hydroxylase for its co-factor and substrate is reduced whereas its Fmax is increased unless the enzyme is purified from neurons that have been stimulated in vivo, suggesting that the neuronal depolarisation in vivo has already caused phosphorylation of the enzyme. This is supported by evidence that the enzyme activation caused by neuronal depolarisation is blocked by a Ca +/calmodulin protein kinase inhibitor. However, whereas depolarisation... 

The signal-mediating function of Ca is performed as a Ca Tcahnodulin complex in many signaling pathways. Ca /catmodulin can bind specifically to effector proteins and modulate their activity. In first place as effector proteins of Ca Tcahnodulin are the /calmodulin protein kinases (CaM kinases) (review Braun and Schuhnan, 1995). The CaM kinases are widespread and are found in practically all cells of mam-... 

Bredt, D. S., Ferris, C. D., and Snyder, S. H. (1992). Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase identification of flavin and calmodulin binding sites. . Biol. Chem. 267, 10976-10981. 

Glutamate-mediated Ca2+ entry through NMDA at the plasma membrane level and mobilization of Ca2+from intracellular stores through PLC-mediated generation of PtdIns-3/J is indispensable for the basal NF-kB activity. Three cytosolic Ca2+ sensors, calmodulin, protein kinases C (PKC), and the p2 l(ras)/phosphatidylinositol 3-kinase (Ptdlns-3K)/Akt pathways, are simultaneously involved in the steps linking the Ca2+ to NF-kB activity (Lilienbaum and Israel, 2003 Marchetti et al., 2004 Lubin et al., 2005). Calmodulin modulates calcineurin, a Ca2+-dependent protein phosphatase, which plays a role in the basal NF-kB activity, whilst stimulation of both the calmodulin kinase II and Akt kinase pathways results in the up-regulation of the transcriptional potential of the p65 subunit of NF-/cB (Lilienbaum and Israel,... 

In primary cultures of neonatal cerebellar granule neurons, all Ca2+ sensors, calmodulin, protein kinases C (PKC), and the p21(ras)/phosphatidylinositol 3 -kinase (Ptdlns-3K)/Akt pathway, converge towards NF-kB at the levels of nuclear translocation as well as transcription. The duration of NF-kB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on the different upstream and downstream signaling associated with various kinases. This is in contrast to studies in non-neuronal cells, which either do not respond to Ca2+ or do not simultaneously activate all three cascades (Lilienbaum and Israel, 2003). Collective evidence suggests that brain inflammatory processes differ from systemic inflammation not only in the involvement of various types of neural cells but also in differences in response to second messengers. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

IP3 diffuses to specialized regions of the endoplasmic reticulum and induces it to release a small amount of stored Ca " (Golovina and Blaustein, 1997). The conse-tfuent increase in cytoplasmic levels stimulates a rtumber of events in the cytoplasm, including the further activation of protein kinase C. Calcium ions directly bind to and activate calmodulin, protein kinase C, phospholipase A2, proteins of muscle fibers (troponin, caldesmon), and proteins of the cytoskeleton (geisolin, villin). One might hesitate to cali these proteins Ca-metalloenzymes. It is more accurate to say that these enzymes are regulated by calcium. 

Yoshida, T., M. Mio and K. Tasaka. Ca2+-induced cortisol secretion from permeabilized bovine adrenocortical cells the roles of calmodulin, protein kinase C and cyclic AMP. Pharmacol. Toxicol. 46 181-192, 1993. 

Ci and calmodulin Ca -calmodulin protein kinase Phosphorylase kinase or glycogen synthase kinase 2... 

Although there were 5 potential sites of phosphorylation by protein kinase C and 2 potential sites of phosphorylation by Ca /calmodulin protein kinase II over the entire sequence, only one of those sites lied in the C-terminal region. The Ser-Pro motifs, where phosphorylation-dephospho-rylation was suggested to play a role in the translocation of the enzyme in animal tissues (Wang et aly 1993 Kalmar et aly 1994), were not found. 

In its dephosphorylated state, synapsin I is thought to crosslink synaptic vesicles to the surrounding cytoskeletal lattice. When synapsin I is phosphorylated its interactions both with the synaptic vesicles and the cytoskeletal elements are reduced, resulting in a dissociation of the vesicles from the cytoskeleton. As a result of this phosphorylation reaction, which is catalyzed by the calcium/ calmodulin protein kinase, CaM-kinase II, more vesicles may become available for fusion with the nerve terminal membrane and, consequently, a greater quantity of neurotransmitter may be released during nerve activity. ... 

---