Ca2+ tunneling architecture and function are important for secretion.

Area of Science:

• Cellular Biology
• Physiology
• Biochemistry

Background:

• Store-operated Ca2+ entry (SOCE) and endoplasmic reticulum (ER) Ca2+ release are critical for cellular calcium homeostasis.
• The precise mechanisms and physiological relevance of Ca2+ tunneling, a process linking SOCE and ER Ca2+ release, remain incompletely understood.

Purpose of the Study:

• To elucidate the spatial organization of Ca2+ tunneling machinery relative to STIM1 upon store depletion.
• To functionally investigate the role of Ca2+ tunneling in physiological processes using a novel inhibitor.

Main Methods:

• High-resolution imaging to visualize the spatial remodeling of key proteins (IP3R1, SERCA, PMCA, Ano1) relative to STIM1.
• Engineering of a Ca2+ tunneling attenuator (CaTAr) to specifically block Ca2+ tunneling without affecting SOCE or Ca2+ release.

Main Results:

• Ca2+ tunneling components redistribute to distinct plasma membrane and cortical ER subdomains following store depletion.
• CaTAr effectively inhibits Ca2+ tunneling, leading to reduced Cl- secretion in sweat gland cells.
• In vivo studies demonstrated that CaTAr reduces sweating in mice, highlighting the physiological importance of Ca2+ tunneling.

Conclusions:

• Ca2+ tunneling involves a dynamic spatial remodeling of signaling components at the plasma membrane and ER.
• Ca2+ tunneling is a fundamental Ca2+ signaling mechanism with significant physiological roles, including regulation of secretion and sweating.
• Targeting Ca2+ tunneling offers a potential avenue for modulating physiological processes.