1. Introduction

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. Indeed, 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 that was able to regulate intracellular calcium spikes^[1]. After protein purification and cDNA isolation, it became clear that P400 was a channel releasing calcium from the endoplasmic reticulum (ER)^[2]. Later, ITPR was shown to be a rather peculiar channel, as two-second messengers are needed for its activation: IP3 and calcium^[3].

2. Functional Role

Three isoforms of ITPR have been identified (ITPR1-3) in mammals, which, albeit produced by different genes, show 70% of homology in the primary protein sequence^[3]. The similarity in amino acid sequence also reflects the resemblance in protein conformation and spatial organization. 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). These domains are organized in a complex tetrameric “mushroom-like” structure, with the stalk inserted in the ER membrane and the cap exposed to the cytosol^[4]. The stalk is mainly represented by the transmembrane TM domain, with its six-helices forming the ion-conducting pore. All the other domains are in the “cap”, exposed to the cytosol. This organization makes the IBC domain available to IP3 binding, and the regulatory domain to the many interactions and post-transcriptional modifications that regulate the receptor activity, including phosphorylation and oxidation^[4]. Nevertheless, the information on the ITPR molecular organization is still not sufficient for a complete mechanistic definition of its structure–function relationship^[5]. If the central calcium conducting pore is similar to other ion channels, as suggested by the 4.7 Å structure of ITPR, 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. The feature of ITPR of being prone to modulation by nearby signals gives an idea of the complexity of the ITPR-interactome. In other words, ITPRs have the structural complexity to participate in and regulate a dense network of cellular processes. ITPRs are differently expressed in human tissues. The effects of ITPRs have been extensively studied in preclinical models.

The function of ITPR has been historically assessed in the neurological field. Indeed, the first identification of P400 protein occurred in Purkinje cells and the neurological signs were the first to be studied in mice. The highest number of ITPR human mutations has been identified in neurological disorders, in particular affecting the isoform 1. Indeed, ITPR1 is the most abundant isoform in the brain, regulating important functions including memory and motor coordination. While an evident role of ITPRs has been recognized for several human pathologies by identifying specific mutations, a potential role of this channel in other human conditions has been suggested by genome whole association studies (GWAS).

For an updated overview of the human pathologies where ITPR alterations have a clear causative role, please refer to our report^[4].