Inositol 1,4,5-trisphosphate receptors and their protein partners as signalling hubs

Abstract

Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are expressed in nearly all animal cells, where they mediate the release of Ca(2+) from intracellular stores. The complex spatial and temporal organization of the ensuing intracellular Ca(2+) signals allows selective regulation of diverse physiological responses. Interactions of IP3 Rs with other proteins contribute to the specificity and speed of Ca(2+) signalling pathways, and to their capacity to integrate information from other signalling pathways. In this review, we provide a comprehensive survey of the proteins proposed to interact with IP3 Rs and the functional effects that these interactions produce. Interacting proteins can determine the activity of IP3 Rs, facilitate their regulation by multiple signalling pathways and direct the Ca(2+) that they release to specific targets. We suggest that IP3 Rs function as signalling hubs through which diverse inputs are processed and then emerge as cytosolic Ca(2+) signals.

Figure 1. Association of proteins with IP₃Rs

Key functional domains of a single IP₃R subunit are shown: the suppressor domain (SD), IP₃‐binding core (IBC), cytosolic regulatory domain, transmembrane domains (TMDs) and the cytosolic C‐terminus (CT). The sites to which proteins are proposed to bind are shown. Many additional proteins are thought to associate with IP₃Rs, but the binding sites have not been identified. Abbreviations and references are provided in Tables 1, 2, 3, 4.

Figure 2. IRBIT controls the sensitivity of IP₃Rs

A, the N‐terminal region of IRBIT includes a serine‐rich domain. Phosphorylation of S68, the ‘master’ phosphorylation site, allows sequential phosphorylation of the two residues, S71 and S74, that must be phosphorylated for IRBIT to bind to IP₃Rs. Protein phosphatase 1 (PP1) bound to IRBIT dephosphorylates S68. B, phosphorylation of IRBIT (1) allows it to bind to the IBC and so compete with IP₃ for binding to the IP₃R. Phospho‐IRBIT thereby sets the sensitivity of the IP₃R to IP₃. IP₃ binding to the IBC (2) prevents IRBIT binding and initiates activation of the IP₃R. The displaced phospho‐IRBIT can regulate many additional targets, including ion channels and transporters (3). The Ca²⁺ released by active IP₃Rs may control the phosphorylation state of IRBIT, and thereby complete a feedback loop that regulates IP₃R sensitivity (4).

Figure 3. A signalling complex assembled around IP₃Rs controls gluconeogenesis

Glucagon and insulin exert opposing effects on hepatic gluconeogenesis. Their signalling pathways converge to a protein complex assembled around IP₃Rs, the activity of which controls phosphorylation of the transcription factor CRTC2. Dephosphorylated CRTC2 translocates to the nucleus, where it associates with CREB and stimulates transcription of genes required for gluconeogenesis. SIK2 phosphorylates CRTC2, while calcineurin dephosphorylates it. Glucagon, via a GPCR, stimulates both PLC and AC. The IP₃ produced by PLC stimulates IP₃Rs. The cAMP generated by AC stimulates PKA and that promotes dephosphorylation of CRTC2 by phosphorylating both SIK2 (inhibiting its activity) and IP₃Rs, sensitizing the latter to IP₃. The larger Ca²⁺ signal then activates calcineurin. Insulin causes activation of AKT1, which phosphorylates IP₃Rs and inhibits their activity; it thereby opposes the effects of glucagon and attenuates calcineurin activity. Phosphorylation is indicated by red circles, black arrows denote stimulation and the red arrow denotes inhibition. Abbreviations and further details in the text and tables.

Figure 4. EB3 is required for effective signalling by IP₃Rs in endothelial cells

In endothelial cells, EB3 binds to a TxIP motif within the regulatory domain of IP₃R3, allowing IP₃Rs to associate with the plus‐end of microtubules. Disrupting this interaction prevents clustering of IP₃Rs and attenuates the Ca²⁺ signals evoked by thrombin, which cleaves within the N‐terminus of PAR‐1 and allows it to stimulate PLC. The evidence (Geyer et al. 2015) suggests that the EB3‐mediated interaction of IP₃R3 with microtubules is essential for the clustering of IP₃Rs that allows the Ca²⁺ released by one IP₃R to be amplified by recruitment of neighbouring IP₃Rs.