Study of IP3 receptor/Ca^<2+> signaling in neural plasticity and brain development and differentiation

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IP_3 is a second messenger to release Ca^<2+> from internal stores. We discovered that P400 which is deficient in Purkinje-neuron-degenerating mutant is IP_3 receptor (IP_3R). IP_3R /P400 is found to be localized on endoplasmic reticulum (ER). Purified IP_3 receptor (IP_3R) works as Ca^<2+> release channel and works as Ca^<2+> oscillator. IP_3R function is regulated by phosphorylation (by PKC, CaMK II, PKG) suggesting that IP_3R works as a cross-talk station between Ca^<2+> signaling and phosphorylation. IP_3R has unique properties: 1) IP_3R is functional even though it is fragmented by proteases into several pieces; 2) IP_3R allosterically and dynamically changes its form reversibly; _3) CryoEM study shows that IP_3R contains multiple cavities; 4) ER forms a meshwork and vesicular ER containing IP_3R moves rapidly along microtubles using kinesin motor. We succeeded in crystallization of IP_3 binding core and suppressor sequence. They show unique structure and interact each other to re … More cognize IP_3. Studies on the role of IP_3R during development show that IP_3R is involved in fertilization and is essential for determination of dorsoventral axis formation. IP_3R is involved in neuronal plasticity. Double homozygous mutant of IP_3R2 and IP_3R_3 shows deficit of exocrine secretion. ERp44 works as a redox sensor in the ER and regulates IP_3R1 activity. We developed IP_3 indicator (named as IRIS) using the IP_3 binding core. We discovered that IP_3 not only releases Ca^<2+>, but also releases IRBIT. IRBIT binds to the same site as IP_3. IRBIT works only when it is phosphorylated. It regulates frequency and amplitude of Ca^<2+> oscillation generated by IP_3R. In addition, phosphorylated IRBIT binds to pancreas type Na, Bicarbonate co-transporter 1 (NBC1) and works as a third messenger to enhance NBC1 which regulates pH inside cells. Therefore, signaling pathway may be modified to be as follows: [ extracellular signal →IP_3→IP_3R→Ca^<2+> release, and IRBIT release→NBC1 activation, and Ca^<2+> oscillation modification ]. Less