Fig. 8

Dysfunctional IP₃R3 subunits impair channel function and T-cell activation. Simplified schematic representation of T-cell activation pathways relevant to the presented results. A T-cell receptor (TCR) stimulation results in the activation of phospholipase C (PLC) γ and the subsequent generation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃) from phosphatidylinositol 4,5-bisphosphate (PIP₂). While DAG activates the Ras/mitogen-activated protein kinase (MAPK) pathway and ultimately phosphorylation of Erk, allowing its nuclear translocation, IP₃ binds to the tetrameric IP₃ receptor (IP₃R). Its activation results in Ca²⁺ (light blue dots) efflux from the endoplasmic reticulum, which in turn activates STIM and the opening of the plasmalemmal ORAI channels that mediate store-operated Ca²⁺ influx. Variants in both of these proteins (dark blue) have been previously described in the human immunodeficiency context. The influx from extracellular Ca²⁺ through ORAI results in an increase in cytosolic Ca²⁺ ([Ca²⁺]_cyt) that results in nuclear translocation of nuclear factor of activated T cells (NFAT) and other effects. These processes result in the transcription of essential genes for cell activation, proliferation, and cytokine production. B Damaging variants of IP₃R3 (dark red subunits) result in impaired function of homo- or heterotetrameric receptor complexes with reduced Ca²⁺ efflux into the cytosol. Reduced signaling via STIM/ORAI and impaired activation of Erk and NFAT pathways are insufficient for adequate lymphocyte activation and manifest in clinical immunodeficiency