Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function

Area of Science:

• Physiology
• Molecular Biology
• Genetics

Background:

• Eccrine sweat glands regulate human thermoregulation through sweating.
• Loss-of-function mutations in CRAC channel genes (ORAI1, STIM1) lead to anhidrosis and hyperthermia.
• These mutations disrupt store-operated calcium entry (SOCE).

Purpose of the Study:

• To investigate the role of CRAC channels and SOCE in sweat gland function.
• To determine the molecular mechanisms underlying sweat production regulated by calcium signaling.

Main Methods:

• Utilized genetically modified mice with tissue-specific deletion of Orai1 or Stim1/2.
• Examined sweat gland development and function in knockout mice and human sweat gland cells.
• Assessed store-operated calcium entry (SOCE) and chloride secretion.
• Investigated the activation of Ca2+-activated chloride channels (CaCCs) like ANO1/TMEM16A.

Main Results:

• CRAC channel-deficient patients and mice exhibited impaired sweating despite normal sweat gland development.
• SOCE was abolished in sweat glands lacking ORAI1 or STIM1/2.
• Absence of SOCE impaired chloride secretion and CaCC activation in murine and human sweat glands.
• Expression of TMEM16A and AQP5 remained normal, indicating a specific role for SOCE in chloride transport.

Conclusions:

• Store-operated calcium influx through CRAC channels is essential for activating CaCCs.
• This process is critical for chloride secretion and overall sweat production in humans and mice.
• CRAC channels represent a key molecular target for understanding and potentially treating disorders of sweat regulation.