Proteolytic fragmentation of inositol 1, 4, 5‐trisphosphate receptors: a novel mechanism regulating channel activity?. (7th December 2015)

• Record Type: Journal Article
• Authors: Wang, Liwei; Alzayady, Kamil J.; Yule, David I.
• Is Part Of: Journal of physiology. Volume 594:Number 11(2016:Jun.)
• Page Start: 2867
• Page End: 2876
• Publication Date: 2015-12-07
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP271140
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Conventional activation of IP3 R results in intracellular Ca 2+ signals with distinct features in terms of amplitude, frequency, initiation sites and duration of the signal as a consequence of regulation of channel activity by numerous cellular factors. In turn, these particular characteristics enable the activation of a specific subset of Ca 2+ effector molecules and physiological outcomes (top panel). In this review we present evidence that proteolytic cleavage of IP3 R by calpain and caspase does not necessary disable the channel, but consider that altered regulation of the cleaved channel may result in the generation of Ca 2+ signals with distinct properties which encode specific cellular outcomes (bottom panel). Abstract: Inositol 1, 4, 5‐trisphosphate receptors (IP3 Rs) are a family of ubiquitously expressed intracellular Ca 2+ release channels. Regulation of channel activity by Ca 2+, nucleotides, phosphorylation, protein binding partners and other cellular factors is thought to play a major role in defining the specific spatiotemporal characteristics of intracellular Ca 2+ signals. These properties are, in turn, believed pivotal for the selective and specific physiological activation of Ca 2+ ‐dependent effectors. IP3 Rs are also substrates for the intracellular cysteine proteases, calpain and caspase. Cleavage of the IP3 R 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 Ca 2+ pore. Contrary to this hypothesis, we demonstrate following proteolysis that N‐ and C‐termini of IP3 R1 remain associated, presumably through non‐covalent interactions. Further, we show that complementary fragments of IP3 R1 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 IP3 R peptide chain may alter other important regulatory events to modulate channel activity. In this scenario, stimulation of the cleaved IP3 R may support distinct spatiotemporal Ca 2+ 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 IP3 R regulation, which plays a role in varied adaptive physiological processes.