Proteolytic fragmentation of inositol 1,4,5‐trisphosphate receptors: a novel mechanism regulating channel activity?

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• 作者：Liwei Wang ; Kamil J. Alzayady ; David I. Yule
• 刊名：The Journal of Physiology
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：594
• 期：11
• 页码：2867-2876
• 全文大小：763.0KB
• ISSN：1469-7793

文摘

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are a family of ubiquitously expressed intracellular Ca²⁺ release channels. Regulation of channel activity by Ca²⁺, nucleotides, phosphorylation, protein binding partners and other cellular factors is thought to play a major role in defining the specific spatiotemporal characteristics of intracellular Ca²⁺ signals. These properties are, in turn, believed pivotal for the selective and specific physiological activation of Ca²⁺-dependent effectors. IP₃Rs are also substrates for the intracellular cysteine proteases, calpain and caspase. Cleavage of the IP₃R has been proposed to play a role in apoptotic cell death by uncoupling regions important for IP₃ binding from the channel domain, leaving an unregulated leaky Ca²⁺ pore. Contrary to this hypothesis, we demonstrate following proteolysis that N- and C-termini of IP₃R1 remain associated, presumably through non-covalent interactions. Further, we show that complementary fragments of IP₃R1 assemble into tetrameric structures and retain their ability to be regulated robustly by IP₃. While peptide continuity is clearly not necessary for IP₃-gating of the channel, we propose that cleavage of the IP₃R peptide chain may alter other important regulatory events to modulate channel activity. In this scenario, stimulation of the cleaved IP₃R may support distinct spatiotemporal Ca²⁺ signals and activation of specific effectors. Notably, in many adaptive physiological events, the non-apoptotic activities of caspase and calpain are demonstrated to be important, but the substrates of the proteases are poorly defined. We speculate that proteolytic fragmentation may represent a novel form of IP₃R regulation, which plays a role in varied adaptive physiological processes.