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Functions of the N-type Ca Channel/14-3-3 Interaction

N型Ca通道的功能/14-3-3相互作用

基本信息

批准号：
8046337
负责人：
YI ZHOU
金额：
$ 28.36万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2014-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The N-type Ca channel, along with the P/Q-type, plays a central role in chemical synaptic transmissions in the nervous system. As these Ca2+ channels determine the amount, timing and location of Ca2+ influx at nerve terminals, changes in Ca2+ channel biophysical properties, especially their inactivation kinetics, can profoundly affect the temporal dynamics of evoked neurotransmitter release. Despite recent advances, there are still major gaps in our understanding of molecular mechanism for Ca2+ channel inactivation, as well as their regulations by signally proteins in neurons. This proposal seeks to understand the cellular and molecular mechanisms of regulation of N-type Ca2+ channels by 14-3-3 proteins, a family of brain-rich proteins that participate in multiple cellular processes. In our preliminary studies, we not only discovered and characterized the novel protein-protein interaction between the N-type Ca2+ channel and 14-3-3, but also determined a profound modulation of inactivation properties of N-type Ca2+ channels by 14-3-3. Furthermore, we revealed a significant change in short-term synaptic plasticity by antagonizing 14-3-3 binding in the presynaptic neuron. In this application, we will build on these findings and further investigate the function and mechanism of this regulatory complex using a combination of molecular, biochemical and electrophysiological techniques. Our specific aims are: (1) Determine the mechanism underlying 14-3-3-dependent modulation of N-type Ca2+ channel inactivation. Specifically, we will investigate whether 14-3-3 modulates inactivation properties of N-type Ca2+ channels through its binding to the channel. (2) Determine the mechanism underlying 14-3-3- dependent modulation of short-term synaptic plasticity. Specifically, we will investigate whether 14-3-3 regulates short-term plasticity by modulating N-type Ca2+ channel inactivation. (3) Determine dynamic interactions between 14-3-3 and N-type Ca2+ channels in neurons. Specifically, we will investigate whether formation of this protein complex is promoted by recurring presynaptic activity, via enhancing CaMKII-dependent phosphorylation of the N-type Ca2+ channel. Together, these studies will provide a novel mechanism for regulation of N-type Ca2+ channels and help to understand 14-3-3's functions in the nervous system.

描述（由申请人提供）：N 型 Ca 通道与 P/Q 型通道一起，在神经系统的化学突触传递中发挥着核心作用。由于这些 Ca2+ 通道决定 Ca2+ 流入神经末梢的数量、时间和位置，因此 Ca2+ 通道生物物理特性的变化，尤其是其失活动力学，可以深刻影响诱发神经递质释放的时间动态。尽管最近取得了进展，但我们对 Ca2+ 通道失活的分子机制及其神经元信号蛋白的调节的理解仍然存在重大差距。该提案旨在了解 14-3-3 蛋白（参与多个细胞过程的富含大脑的蛋白家族）调节 N 型 Ca2+ 通道的细胞和分子机制。在我们的初步研究中，我们不仅发现并表征了N型Ca2+通道和14-3-3之间的新型蛋白质-蛋白质相互作用，而且还确定了14-3-3对N型Ca2+通道失活特性的深刻调节。此外，我们发现通过拮抗突触前神经元中的 14-3-3 结合，短期突触可塑性发生显着变化。在此应用中，我们将在这些发现的基础上，结合分子、生化和电生理学技术进一步研究这种调节复合物的功能和机制。我们的具体目标是： (1) 确定 N 型 Ca2+ 通道失活的 14-3-3 依赖性调节的潜在机制。具体来说，我们将研究 14-3-3 是否通过与通道结合来调节 N 型 Ca2+ 通道的失活特性。 (2) 确定短期突触可塑性的 14-3-3 依赖性调节的潜在机制。具体来说，我们将研究 14-3-3 是否通过调节 N 型 Ca2+ 通道失活来调节短期可塑性。 (3)确定神经元中14-3-3和N型Ca2+通道之间的动态相互作用。具体来说，我们将研究重复的突触前活动是否通过增强 N 型 Ca2+ 通道的 CaMKII 依赖性磷酸化来促进这种蛋白质复合物的形成。总之，这些研究将为 N 型 Ca2+ 通道的调节提供一种新的机制，并有助于了解 14-3-3 在神经系统中的功能。