STIM1 and lipid interactions at ER-PM contact sites.

Store-operated calcium (Ca²⁺) entry (SOCE) represents a major route of Ca²⁺ permeation across the plasma membrane (PM) in nonexcitable cells, which plays an indispensable role in maintaining intracellular Ca²⁺ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca²⁺ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca²⁺ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to the translocation of activated STIM1 toward the PM. This movement is facilitated by the physical interactions between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca²⁺ signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Finally, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca²⁺ signaling at ER-PM MCSs.