Calcium/calmodulin-dependent protein kinases inhibition

See, V., Boutillier, A. L., Bito, H. and Loeffler, J. P., 2001, Calcium/calmodulin-dependent protein kinase type TV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons, Faseb J, 15, pp 134-144. 

Chum S. B., Taft W. C., Billingsley M. S., Blair R. E., and DeLorenzo R. J. (1990) Temperature modulation of ischemic neuronal death and inhibition of calcium/ calmodulin-dependent protein kinase II in gerbils. Stroke 21,1715-1721. 

In addition, vinpocetine selectively inhibits a specific calcium, calmodulin-dependent cycHc nucleotide phosphodiesterase (PDF) isozyme (16). As a result of this inhibition, cycHc guanosine 5 -monophosphate (GMP) levels increase. Relaxation of smooth muscle seems to be dependent on the activation of cychc GMP-dependent protein kinase (17), thus this property may account for the vasodilator activity of vinpocetine. A review of the pharmacology of vinpocetine is available (18). 

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. 

At micromolar concentrations opioids cause an increase in the cell membrane threshold, shortened action potentials, and inhibition of neurotransmitter release. At nanomolar concentrations opioid agonists are excitatory and prolong the action potential via the stimulatory G proteins, which act on the adenylate cyclase/cAMP system and on protein kinase A-dependent ion channels. Tolerance is proposed to be the result of an increase in the association of opioid receptors to stimulatory G proteins, to an activation of A-methyl-o-aspartate receptors via protein kinase C, and calmodulin-dependent increases in cytosolic calcium, resulting in cellular hyperexcitability. 

Calmodulin dependent Kinases. Calmodulin-dependent kinases further relay and amplify the calcium signal from calmodulin to their target proteins. In animals, the identified calmodulin-dependent kinases include CaM-dependent kinase kinase (CaMKK), CaM kinase I-IV (CaMKI-IV), in which CaMKII is also known as elongation factor-2 kinase (eEF 2K), MLCKs and so on. CaMKK, CaMKI, CaMKII, and CaMKIV have multiple targets that involve them in multiple activities, while eEF-2K and MLCK have much more restricted targets. CaMKK is at the upstream of the CaMKI and CaMKIV kinase cascade. CaMKK activates CaMKI and CaMKIV through the phosphorylation of these two kinases. The other substrate for CaMKK is protein kinase B (PKB). The activity of CaMKK itself is inhibited by protein... 

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