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.