Abstract
Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.
Highlights
Since their discovery in the 1970s, several studies have provided substantial evidence that inositol1,4,5-trisphosphate receptors (ITPRs) play a pleiotropic role in the regulation of cellular functions.their ability to regulate calcium handling poses ITPRs at the heart of molecular networks underlying cellular homeostasis: From proliferation, apoptosis, and differentiation to metabolism and neurotransmission.ITPR was identified for the first time as a large membrane protein called P400 [1,2] that was able to regulate intracellular calcium spikes [1,2,3]
If the central calcium conducting pore is similar to other ion channels, as suggested by the 4.7 Å structure of ITPR [16], the spatial arrangement of the cytosolic C-terminus is quite unique for ITPR; in particular, these carboxyl tails have the ability to interact with the N-terminal domains of the near subunits, suggesting a mechanism of allosteric regulation dictated by intracellular signals [16]
Ferreiro et al demonstrated that antibody-aggregates are able to induce calcium release by ITPR in cortical neurons, leading to apoptosis, which was prevented by the ITPR inhibitor Xestopongin C [62]
Summary
Since their discovery in the 1970s, several studies have provided substantial evidence that inositol. 1,4,5-trisphosphate receptors (ITPRs) play a pleiotropic role in the regulation of cellular functions. All three isoforms consist of five domains: Suppressor domain (SD), IP3 binding core domain (IBC), regulatory domain, transmembrane domain (TD), and C-terminus domain (CTD) [14,15,16,17]. These domains are organized in a complex tetrameric “mushroom-like” structure (Figure 1), with the stalk inserted in the ER membrane and the cap exposed to the cytosol [18]. Med. 2020, 9, 1096; doi:10.3390/jcm9041096 www.mdpi.com/journal/jcm potential strategy to prevent motor neuron deterioration in ALS [73]
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