CALCIUM CHANNELS IN NON EXCITABLE CELLS

钙(Ca)是一种关键的信号分子，参与了许多 包括T细胞激活、平滑肌在内的调节通路 收缩、激素释放、细胞生长和分化以及 受精。三磷酸肌醇受体(LP3R)是 不可兴奋细胞的主要细胞内钙释放通道，在许多 刺激质膜受体诱导产生lP3的病例 这激活了lP3R，从细胞内的存储中释放出钙。尽管 LP3-门控性钙通道的核心重要性仍有待进一步研究 了解了如何监管渠道。我们已经克隆了完整的 从T淋巴细胞(Jurkat)获得编码人类1型lP3R(LP3R1)的基因。 我们已经确定了推测的酪氨酸磷酸化位点 IP3R1的氨基酸序列，表明该通道为酪氨酸 激活的T中的磷酸化并与Fyn发生物理关联 细胞。此外，我们还证明了fyn对酪氨酸的磷酸化 增加平面脂双层中lP3R的开放几率。更多 最近，我们已经能够表达具有功能的人重组IP3R1 在适合于表征通道的异源系统中 属性。这些观察结果使我们提出以下问题 问题：1)lP3R1中哪些残基是酪氨酸磷酸化的；2) LP3R1与src家族成员的SH2结合域相互作用 3)IP3R1的酪氨酸磷酸化是否会改变钙离子浓度？ 通道的激活和失活的敏感性；以及4)什么 是src家族激酶(包括fyn和lck)在 调节T淋巴细胞中的lP3R1？这些研究应该导致小说的产生 关于酪氨酸的分子机制的信息 磷酸化调节IP3R1的功能。了解IP3R法规 应该提供对潜在信号通路的洞察力 免疫抑制、癌症、节育、 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.