INOSITOL 1,4,5 TRIPHOSPHATE RECEPTOR (IP3R)

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肌醇1,4,5-三磷酸受体（IP3Rs）是由肌醇1,4,5-三磷酸（IP3）控制的细胞内Ca2+释放通道。这些通道允许Ca2+离子从内质网快速流动，从而在神经递质释放、受精、激素分泌、基因转录、代谢调节和细胞凋亡中发挥关键作用。在哺乳动物中，有3种不同的IP3R基因表达，同源性约为70%。单个细胞类型可以表达一种以上的同工异构体，它们可以形成同工或异工四聚体群体。1型IP3R （IP3R1）是小脑内质网（ER）的主要类型，形成同源四聚体，Mr大于1.2 MDa。小脑通常被用作纯化IP3R1的主要来源，用于结构-功能表征。该项目的长期目标是通过对IP3R通道复合物的结构-功能分析，确定ip3诱导的Ca2+门控的分子机制，并确定该通道蛋白的缺陷如何导致细胞Ca2+水平的异常调节，从而导致人类疾病，如心脏肥厚、心力衰竭、遗传性共济失调、骨质疏松、动脉粥样硬化和某些偏头痛。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are the intracellular Ca2+ release channels gated by inositol 1,4,5-trisphosphate (IP3). These channels allow rapid fluxes of Ca2+ ions from the endoplasmic reticulum, thereby playing a key role in neurotransmitter release, fertilization, hormone secretion, gene transcription, metabolic regulation and apoptosis. In mammals, 3 different IP3R genes, sharing ~70% homology, are expressed. Individual cell types can express more than one isoform, and they may form homo- or hetero-tetrameric populations. The type 1 IP3R (IP3R1) is the predominant type in the cerebellar endoplasmic reticulum (ER), forming homo-tetramers with a Mr over 1.2 MDa. The cerebellum is generally used as a primary source for purification of the IP3R1 for structure-function characterization. The long-term objectives of this project are to determine the molecular mechanisms of the IP3-induced Ca2+-gating through structure-function analysis of the IP3R channel complex and to define how defects in this channel protein can cause abnormal regulation of cell Ca2+ level underlying human diseases such as cardiac hypertrophy, heart failure, hereditary ataxias, osteoporosis, atherosclerosis and some migraines.