CALCIUM CHANNELS IN NON EXCITABLE CELLS

钙（Ca）是一种重要的信号分子，参与了许多 调节途径，包括T细胞活化、平滑肌 收缩，激素释放，细胞生长和分化， 受精肌醇1，4，5-三磷酸受体（IP 3R）是肌醇受体。 在非兴奋性细胞中主要的细胞内钙释放通道，在许多 例刺激质膜受体诱导产生lP 3 激活IP 3R从细胞内储存中释放钙。尽管 IP 3门控Ca通道的核心重要性，还有很多工作要做。 了解了该渠道是如何监管的。我们克隆了完整的 来自T淋巴细胞（Jurkat）的编码人1型IP 3R（IP 3R 1）的cDNA。 我们已经确定了推定的酪氨酸磷酸化位点， IP 3R 1的氨基酸序列，并显示通道是酪氨酸 磷酸化，并在激活的T细胞中与fyn发生物理联系。 细胞此外，我们已经表明，酪氨酸磷酸化的fyn 增加了IP 3R在平面脂质双层中的开放概率。更 最近，我们已经能够表达功能性人重组IP 3R 1 在适于表征通道异源系统中 特性.这些观察使我们提出以下问题 问题：1）哪些残基在IP 3R 1中被酪氨酸磷酸化; 2） IP 3R 1与src家族成员的SH 2结合结构域相互作用 激酶; 3）IP 3R 1的酪氨酸磷酸化是否改变了Ca- 对通道的激活和失活的敏感性;以及4）什么 src家族激酶（包括fyn和lck）在 调节T淋巴细胞中的lP 3R 1？这些研究将导致新的 关于酪氨酸的分子机制的信息 磷酸化调节IP 3R 1功能。 了解IP 3R法规 应该可以提供对信号通路的深入了解， 用于免疫抑制、癌症、生育控制、 高血压和中风。

Calcium (Ca) serves as a critical signaling molecule involved in numerous regulatory pathways including T cell activation, smooth muscle contraction, hormone release, cell growth and differentiation and fertilization. The inositol 1 ,4,5-trisphosphate receptor (lP3R) is the major intracellular Ca release channel in non-excitable cells, In many cases stimulation of a plasma membrane receptor induces generation of lP3 that activates the lP3R to release Ca from intracellular stores. Despite the central importance of the lP3-gated Ca channel, much remains to be learned about how the channel is regulated. We have cloned the complete cDNA encoding the human type 1 lP3R (lP3R1) from T lymphocytes (Jurkat). We have identified putative tyrosine phosphorylation sites in the deduced amino acid sequence of IP3R1 and shown that the channel is tyrosine phosphorylated and becomes physically associated with fyn in activated T cells. Moreover, we have shown that tyrosine phosphorylation by fyn increases the open probability of lP3R in planar lipid bilayers. More recently, we have been able to express functional human recombinant IP3R1 in heterologous systems that are suitable for characterization of channel properties. These observations have lead us to ask the following questions: 1) which residues are tyrosine phosphorylated in lP3R1; 2) does lP3R1 interact with the SH2 binding domain of members of the src family kinases; 3) does tyrosine phosphorylation of IP3R1 alter the Ca- sensitivity for activation and inactivation of the channel; and 4) what are the relative roles of src family kinases (including fyn and lck) in regulating lP3R1 in T lymphocytes? These studies should lead to novel information regarding the molecular mechanisms by which tyrosine phosphorylation regulates IP3R1 function. Understanding IP3R regulation should provide insights into signaling pathways that are potential therapeutic targets for immunosuppression, cancer, birth control, hypertension, and stroke.