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. 2018 Jun;6(1-2):29-44.

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

Lara E Terry  1 , Kamil J Alzayady  1 , Esraa Furati  1 , David I Yule  1
Affiliations

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

Lara E Terry et al. Messenger (Los Angel). 2018 Jun.

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.

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Figures

Figure 1.
Figure 1.. IP3R Structure.
Ribbon structure of two IP3R1 subunits as determined by cryo-EM (PDB: 3JAV). The four domains of the IP3R (suppressor, ligand binding, regulatory, and c-terminal), as well as other important structural landmarks, are indicated.
Figure 2.
Figure 2.. IP3R Disease-associated mutations.
The location of IP3R mutations associated with ataxia (dark blue), head and neck squamous cell carcinoma (black), Sézary Syndrome (purple), Gillespie Syndrome (red), generalized anhidrosis (green), and pontine cerebellar hypoplasia (light blue) are indicated on a linear version of the IP3R structure. As illustrated, the IRBIT binding domain spans the IP3R ligand binding domain and a fraction of the regulatory domain, while the CARP binding domain is located solely in the regulatory domain.
See this image and copyright information in PMC

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