Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44
Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44
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DOI：
10.1016/j.cell.2004.11.048
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发表时间：
2005-01-14
期刊：
影响因子：
64.5
通讯作者：
Mikoshiba, K
中科院分区：
文献类型：
--
作者：
Higo, T;Hattori, M;Mikoshiba, K
肌醇1，4，5-三磷酸受体(IP(3)Rs)是介导内质网(ER)钙释放的细胞内通道蛋白，参与多种生物学过程和疾病。IP(3)受体受多种胞质蛋白的差异性调节，但其受内质网管腔蛋白(S)的调节仍未得到很大程度的研究。在本研究中，我们发现硫氧还蛋白家族的内质网蛋白ERp44直接与IP3R 1型(IP(3)R1)的第三腔环相互作用，并且这种相互作用依赖于pH、Call浓度和氧化还原状态：环中需要存在游离的半胱氨酸残基。钙离子成像实验和平面脂质双层系统对IP3R1活性的单通道记录表明，ERp44直接抑制了IP3R1的活性。因此，ERp44感知内质网管腔内的环境，并相应地调节IP3R1的活性，这反过来应该有助于调节管腔内的条件和胞浆钙离子浓度的复杂模式。
Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are intracellular channel proteins that mediate Ca2+ release from the endoplasmic reticulum (ER) and are involved in many biological processes and diseases. IP(3)Rs are differentially regulated by a variety of cytosolic proteins, but their regulation by ER lumenal protein(s) remains largely unexplored. In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP3R type 1 (IP(3)R1) and that the interaction is dependent on pH, Call concentration, and redox state: the presence of free cysteine residues in the loop is required. Ca2+-imaging experiments and single-channel recording Of IP3R1 activity with a planar lipid bilayer system demonstrated that IP3R1 is directly inhibited by ERp44. Thus, ERp44 senses the environment in the ER lumen and modulates IP3R1 activity accordingly, which should in turn contribute to regulating both intralumenal conditions and the complex patterns of cytosolic Ca2+ concentrations.