The key proteins mediating store-operated Ca 2+ entry (SOCE) are the endoplasmic reticulum (ER) Ca 2+ sensor STIM1 and the plasma membrane Ca 2+ -selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (K ex ≃0.1 min −1

SummaryStore-operated calcium entry (SOCE) represents a major calcium influx pathway in non-excitable cells and is central to many physiological processes such as T cell activation and mast cell degranulation. SOCE is activated through intricate coordination between the Ca 2+ sensor on the ER membrane (stromal interaction molecule 1, STIM1) and the plasma membrane channel Orai1. When Ca 2+ stores are depleted, STIM1 oligomerizes and physically interacts with Orai1 through its SOAR/CAD domain, resulting in Orai1 gating and Ca 2+ influx. Here, we describe novel inter-and intramolecular FRET sensors in the context of the full-length membrane-anchored STIM1, and show that STIM1 undergoes a conformational change in response to store depletion to adopt a stretched 'open' conformation that exposes SOAR/CAD and allows it to interact with Orai1. Mutational analyses reveal that electrostatic interactions between the predicted first and third coiled-coil domains of STIM1 are not involved in maintaining the 'closed' inactive conformation. In addition, the results argue that an amphipathic a-helix between residues 317 and 336 in the so-called inhibitory domain is important to maintain STIM1 in a closed conformation at rest. Indeed, mutations that alter the amphipathic properties of this helix result in a STIM1 variant that is unable to respond to store depletion in terms of forming puncta, translocation to the cortical ER or activating Orai1.

A chaperone complex (CCT) regulates the trafficking of a calcium channel (Orai1) and, as such, modulates cellular function.

This report describes the discovery of a human anterior gradient 2 deficiency causing monogenic infantile inflammatory bowel disease resulting from goblet cell depletion and a mucus barrier defect.

Background:The role of the vascular IP 3 receptor (IP 3 R) in hypertension is unknown. Results: IP 3 R are up-regulated in vascular smooth muscle (VSM) in hypertension through the calcineurin-NFAT pathway. Conclusion: Up-regulated IP 3 R in VSM sensitize Ca 2ϩ release and enhance contraction. Significance: Up-regulated vascular IP 3 R may contribute to vascular resistance in hypertension.