The complex regulatory function of the ligand-binding domain of the inositol 1,4,5-trisphosphate receptor

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• 作者：Benoit Devogelaere ; Leen Verbert ; Jan B. Parys ; Ludwig Missiaen ; Humbert De Smedt
• 关键词：Calcium signalling ; IP3 ; IP3 receptor ; Calcium ; Calmodulin ; IRBIT ; Homer ; ERK
• 刊名：Cell Calcium
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：43
• 期：1
• 页码：17-27
• 全文大小：279 K

文摘

The inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) can be divided in three functionally distinct regions: a ligand-binding domain, a modulatory domain and a channel domain. Numerous regulatory mechanisms including inter- and intra-molecular protein–protein interactions and phosphorylation events act via these domains to regulate the function of the IP₃R. Regulation at the level of the ligand-binding domain primarily affects the affinity for IP₃. The extent of IP₃-induced Ca²⁺ release (IICR) is, however, not only determined by the affinity for IP₃ but also by the effectiveness of the coupling between ligand binding and channel opening. As a result, regulation as well as malfunction of IICR may be affected by both steps in the activation mechanism. The 3D structures of the two subdomains of the ligand-binding domain have recently been determined by X-ray diffraction analysis. This allows a more detailed molecular explanation of the regulatory events situated at the ligand-binding domain of the IP₃R. In this review, we will focus on recent structural and functional data on the ligand-binding domain that have extended and clarified the view on the molecular mechanisms of IP₃R regulation.