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

IP3受体/Ca^2信号在神经可塑性和脑发育分化中的研究

• 批准号: 15100006
• 负责人: MIKOSHIBA Katsuhiko
• 金额: $ 77.04万
• 依托单位: The Institute of Physical and Chemical Research (2007)The University of Tokyo (2003-2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15100006/
• 关键词: IP_3 receptor; Ca^<2+> signaling; neuronal plasticity; endoplasmic reticulum; redox sensor; Ip_ indicator; Na+K+-ATPase; 2-APB; 2型,3型IP_3レセプターダブルノックアウトマウ; IP_3レセプター; プルキンエ細胞; 酸・塩基平衡; ナトリウム重炭酸イオン共輸送体1; カルシウム振動; カルシウム; カルシウムチャンネル; 小胞体; ERp4

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

IP_3 是从内部储存释放 Ca^<2+> 的第二信使 我们发现浦肯野神经元变性突变体中缺乏的 P400 是 IP_3 受体 (IP_3R /P400) 定位在内质网上。纯化的IP_3受体(IP_3R)作为Ca^<2+>释放通道并作为Ca^<2+>发挥作用。 IP_3R 功能受磷酸化（通过 PKC、CaMK II、PKG）调节，表明 IP_3R 作为 Ca^<2+> 信号传导和磷酸化之间的串扰站发挥作用：1) IP_3R 具有功能。它被蛋白酶分裂成几个片段；2) IP_3R 变构并可逆地动态改变其形式；_3) CryoEM研究表明IP_3R包含多个空腔；4) ER形成网状结构，并且含有IP_3R的囊泡ER利用驱动蛋白马达沿着微管快速移动，它们显示出独特的结构并相互相互作用。 … 更多认知 IP_3 对 IP_3R 在发育过程中的作用的研究表明，IP_3R 参与受精，对于确定 IP_3R 至关重要。 IP_3R 的形成参与神经元可塑性。IP_3R2 和 IP_3R_3 的双纯合突变体显示外分泌分泌缺陷，并使用 IP_3 开发 IP_3R1 活性。我们发现IP_3不仅释放Ca^<2+>，而且还释放IRBIT。 IRBIT 与 IP_3 结合至同一位点，仅当其被磷酸化时才起作用。此外，磷酸化的 IRBIT 与胰腺 Na 型碳酸氢盐协同转运蛋白 1 结合。 (NBC1) 并作为第三信使增强 NBC1 调节细胞内的 pH 值，因此，信号通路可修改如下： [ 细胞外信号。 →IP_3→IP_3R→Ca^<2+>释放，IRBIT释放→NBC1激活，Ca^<2+>振荡修饰]。

项目成果

Organelles containing inositol trisphosphate receptor type 2 in adrenal medullary cells

• DOI: 10.2170/physiolsci.rp006406
• 发表时间: 2006-12-01
• 期刊: JOURNAL OF PHYSIOLOGICAL SCIENCES
• 影响因子: 2.3
• 作者: Endo，Yutaka;Harada，Keita;Inoue，Masumi
• 通讯作者: Inoue，Masumi

IP_3 receptors/Ca^<2+> channel : role in cell function

IP_3受体/Ca^<2>通道：在细胞功能中的作用

• 发表时间: 2007
• 作者: Mikoshiba;K.
• 通讯作者: K.

Lateral diffusion of inositol 1,4,5-trisphosphate recepter type 1 is regulated by actin filaments and 4.1N in neuronal dendrites.

肌醇 1,4,5-三磷酸受体 1 型的横向扩散受神经元树突中的肌动蛋白丝和 4.1N 调节。

• 发表时间: 2004
• 期刊: J. Biol. Chem 279
• 作者: Fukatsu;K.
• 通讯作者: K.

Long-term potentiation and long-term depression in hippocampal CAI neurons of mice lacking the IP3 type l receptor.

缺乏 IP3 l 型受体的小鼠海马 CAI 神经元的长期增强和长期抑制。

• 发表时间: 2003
• 期刊: Neuroscience 117
• 作者: Nagase;T.;Ito;K. -I.;Kato;K.;Kaneko;K.;Kohda;K.;Matsumoto;M.;Hoshino;A.;Inoue;T.;Fujii;S.;Kato;H.;Mikoshiba;K.
• 通讯作者: K.

Lithium and Calcium ion on Neurodevelopment

锂和钙离子对神经发育的影响

• 发表时间: 2007
• 作者: 田中 慎一郎;小出 博史;表 冴子;Mikoshiba K.
• 通讯作者: Mikoshiba K.