［総説］Ca^<2+>/ カルモデュリン依存性タンパク質リン酸化反応による細胞機能の制御

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  • Regulation of Cell Functions by Ca^<2+>/Calmodulin-Dependent Protein Phosphorylation

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Intracellular Ca^<2+> has been reported to play a critical role in various cellular functions. Many effects of Ca^<2+> are mediated through calmodulin (CaM), and the effects of Ca^<2+>/CaM may be mediated by Ca^<2+>/CaM-dependent protein kinase II (CaM kinase II). Four subunits of CaM kinase II are encoded by distinct genes, and various isoforms of these subunits exist as different splicing variants. In this review, I will focus on the subcellular localizations of major isoforms in neurons and pancreatic $ \beta $ cells and their physiological functions. CaM kinase II is abundant in neurons, comprising 1-2% of the total protein concentration. $ \alpha $ isoform is the most abundant isoform of CaM kinase II in neurons in hippocampal CA1 region. In this region, $ \alpha $ isoform is distributed in the cytoplasm in postsynapse and translocates to postsynaptic density (PSD) following its activation. There are many evidence demonstrating that $ \alpha $ isoform in PSD plays an imiportant role in synaptic plasticity. $ \alpha $B and $ \delta $3 isoforms contain a nuclear localization signal and are localized in the nucleus. Both lsoforms are involved in gene expression. In addition to PSD, $ \alpha $ isoform is associated with synaptic vesicle membranes in presynapse. In the case of insulinoma cells derived from pancreatic $ \beta $ cells, we found that $ \delta 2 isoform is associated with insulin secretory granule membranes. $ \alpha $ isoform and $ \delta $ 2 isoform are involved in neurotransmitter release and insulin secretion, respectively. These results suggest that each isoform is localized in the specific regions in the cells to play an important role in the specific cellular functions. Interestingly, the accumulation of $ \alpha $ isoform has been noted in neuronal soma in Alzheimer's disease brain. Our recent data suggest that $ \alpha $ isoform hyperphosphorylates tau in neuronal soma in Alzheimer's disease brain. Therefore, disturbance of physiological functions of $ \alpha $ isoiorm may be related to the pathophysiology of Alzheimer's disease.

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