Arriving at the next level of complexity in IP₃R and SOCE signaling

The endoplasmic reticulum (ER) has long been recognized as the master regulator of cellular Ca²⁺ signaling. In this context, IP₃R channels may be envisioned as this conductor's baton, which enables virtuous orchestration of cellular Ca²⁺ signaling tunes. IP₃Rs serve the generation of spatiotemporally defined Ca²⁺ changes and are key for the ER´s function as an autonomous Ca²⁺ signaling unit, which is able to govern its own refilling from the extracellular Ca²⁺ pool. As yet, IP₃R signaling has been primarily attributed to its precisely-tunable Ca²⁺ channel function and IP₃-mediated control over Ca²⁺ levels within signaling domains. A recent report from the Hasan laboratory [1] provides evidence for an as yet overlooked function of IP₃R1 in terms of supporting STIM/Orai-mediated SOCE in neurons. IP₃R1 is demonstrated to remarkably facilitate productive STIM-Orai interactions and SOCE by a process that is triggered by IP₃ but independent of the receptors' function as an ER Ca²⁺ channel.