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Inositol 1,4,5-trisphosphate Receptor Mutations associated with Human Disease.

ABSTRACT: Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP3R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mutations, as well as the associated symptoms. Additionally, we use clues from transgenic animals, receptor stoichiometry, and domain location of mutations to speculate on the effects of individual mutations on receptor structure and function and the overall mechanism of disease.

SUBMITTER: Terry LE

PROVIDER: S-EPMC6128530 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Inositol 1,4,5-trisphosphate Receptor Mutations associated with Human Disease.

Terry Lara E LE Alzayady Kamil J KJ Furati Esraa E Yule David I DI

Messenger (Los Angeles, Calif. : Print) 20180601 1-2

Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP<sub>3</sub>R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP<sub>3</sub>R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mut ...[more]

PMID: 30197841

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Project description:Osteoclast activity is central to balanced bone turnover to maintain normal bone mass. A specialized osteoclast attachment to bone localizes acid secretion to remove bone mineral; in some cases, attachment is functionally impaired despite normal attachment proteins. The inositol-1,4,5-trisphosphate receptor-1 (IP3R1) is an intracellular calcium channel required for regulation of reversible osteoclast attachment by nitric oxide (NO), an important regulator of both normal and pathological bone degradation. In studies using human osteoclasts produced in vitro, we found that IP3R1 binds an endosomal isoform of the IP3R-associated cGMP-dependent kinase substrate (IRAG). IRAG is a substrate of cGMP-dependent kinase-1 (PKG1) and binds the PKG1 isoform PKG1β, which was the predominant form of PKG1 in human osteoclasts. Western blots of IRAG were consistent with NO-dependent serine phosphorylation of IRAG. An additional effect of PKG1β activity in osteoclasts was disassociation of IP3R1-IRAG complexes, as shown by analysis of IP3R1 complexes and by localization of the proteins within cells. IP3R1-IRAG complexes were stabilized by PKG or Src antagonists, Src activity being a requirement for IP3R1 calcium release downstream of PKG. IP3R1-mediated calcium release regulates cellular detachment in part through the calcium-dependent proteinase μ-calpain. In osteoclasts with IRAG suppressed by siRNA, activity of μ-calpain was increased relative to cells with normal IRAG, and regulation of μ-calpain by NO was lost. Furthermore, cells deficient in IRAG detached easily from substrate and had smaller attached diameters and randomly distributed podosomes, although IRAG knockdown did not affect cell viability. Our results indicate that IRAG is required for PKG1β-regulated cyclic calcium release during motility, and that disruption of the IP3R1-IRAG calcium regulation system is a novel cause of dysfunctional osteoclasts unrelated to defects in attachment proteins or acid secretion.

Dataset Information

Inositol 1,4,5-trisphosphate Receptor Mutations associated with Human Disease.

Publications

Inositol 1,4,5-trisphosphate Receptor Mutations associated with Human Disease.

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