Calmodulin-Dependent Protein Kinase (CaM Kinase) Inhibitors
Many effects of Ca2+ are mediated by Ca2+/calmodulin(CaM)- dependent protein kinases (CaM kinases). CaM kinases constitute a family of structurally related enzymes that include phosphorylase kinase, myosin light chain kinase, and CaM kinases I-IV. CaM kinase II, one of the best-studied multifunctional enzymes, is found in high concentrations in neuronal synapses, and in some regions of the brain it may constitute up to 2% of the total protein content. Activation of CaM kinase II has been linked to memory and learning processes in the vertebrate nervous system. CaM kinase II is a complex of about 12 subunits that exist in four differentially expressed forms (a, b, g, and d). The a and b isoforms are most abundant in neurons, whereas d or g isoforms are expressed in most tissues. The d isoform is the most prominent isoform in cardiomyocytes. In the inactive state there is a strong interaction between the inhibitory and catalytic domains of the enzyme. The binding of Ca2+/CaM allows the catalytic domain to phosphorylate the inhibitory domain. Once activated, CaM kinase II retains significant activity even after the withdrawal of Ca2+, thereby prolonging the duration of kinase activity. Several synthetic and naturally occurring compounds have been shown to bind CaM in a Ca2+-dependent manner and block the activation of CaM-dependent enzymes. These compounds have been extensively used in investigating the mechanism of Ca2+-binding and activation in biological systems.
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