IP(3)R at ER-Mitochondrial Contact Sites: Beyond the IP(3)R-GRP75-VDAC1 Ca(2+) Funnel

Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca(2+) homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca(2+) transfer unit at ERMCS. These are often reported to form a Ca(2+) funnel that fuels the mitochondrial low-affinity Ca(2+) uptake system. We assess the available evidence on the IP(3)R subtype selectivity at the ERMCS and consider if IP(3)Rs have other roles at the ERMCS beyond providing Ca(2+). Growing evidence suggests that all three IP(3)R subtypes can localise and regulate Ca(2+) signalling at ERMCS. Furthermore, IP(3)Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca(2+) at these sites. Evidence that various binding partners regulate the assembly and Ca(2+) transfer at ERMCS populated by IP(3)R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca(2+) microdomain that is required to fuel mitochondrial Ca(2+) uptake.