STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx.

Area of Science:

• Cellular Biology
• Molecular Signaling
• Calcium Homeostasis

Background:

• Calcium (Ca2+) signaling in nonexcitable cells is initiated by receptor-triggered inositol-1,4,5-trisphosphate production and intracellular Ca2+ release.
• A critical, yet poorly understood, mechanism senses Ca2+ store depletion to activate plasma membrane Ca2+ channels, sustaining Ca2+ signals essential for physiological processes like T cell activation.

Purpose of the Study:

• To identify the key signaling proteins involved in sensing Ca2+ store depletion and mediating Ca2+ influx.
• To elucidate the mechanism by which Ca2+ store depletion triggers sustained Ca2+ signals in nonexcitable cells.

Main Methods:

• Utilized siRNA screening against 2,304 human signaling proteins to monitor receptor-triggered Ca2+ signals.
• Investigated the localization and function of identified proteins, including STIM1, using point mutations and observing cellular responses to Ca2+ store depletion.

Main Results:

• Identified Stromal Interaction Molecule 1 (STIM1) and STIM2 as essential proteins for Ca2+ influx following Ca2+ store depletion.
• Demonstrated that STIM1 translocates to puncta near the plasma membrane upon Ca2+ store depletion.
• Showed that a mutated STIM1 lacking Ca2+ binding ability fails to respond to store depletion, confirming the role of Ca2+ binding in its function.

Conclusions:

• STIM proteins act as direct sensors of Ca2+ levels within the endoplasmic reticulum lumen.
• STIM proteins are critical components of the signaling pathway linking Ca2+ store depletion to the activation of plasma membrane Ca2+ channels.
• This discovery provides a molecular basis for understanding sustained Ca2+ signaling in various cellular functions.