Calmodulin kinases: essential regulators in health and disease

Abstract

Abstract Neuronal activity induces intracellular Ca 2+ increase, which triggers activation of a series of Ca 2+ ‐dependent signaling cascades. Among these, the multifunctional Ca 2+ /calmodulin‐dependent protein kinases (Ca MK s, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated Ca MK s for these roles in neuronal functions are Ca MKI , Ca MKII , Ca MKIV and we will shed light on these neuronal Ca MK s’ functions in this review. Catalytically active members of Ca MK s currently are Ca MKI , Ca MKII , Ca MKIV and Ca MKK . Although they all necessitate the binding of Ca 2+ and calmodulin complex (Ca 2+ /CaM) for releasing autoinhibition, each member of Ca MK has distinct activation mechanisms—autophosphorylation mediated autonomy of multimeric Ca MKII and Ca MKK ‐dependent phosphoswitch‐induced activation of Ca MKI or Ca MKIV . Furthermore, each Ca MK shows distinct subcellular localization that underlies specific compartmentalized function in each activated neuron. In this review, we first summarize these molecular characteristics of each Ca MK as to regulation and subcellular localization, and then describe each biological function. In the last section, we also focus on the emerging role of Ca MK s in pathophysiological conditions by introducing the recent studies, especially focusing on drug addiction and depression, and discuss how dysfunctional Ca MK s may contribute to the pathology of the neuropsychological disorders. This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry” . image