Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

- Store-operated Ca2+ entry (SOCE) is required for sweat gland function in humans and mice.
- Defects in ORAI1 and STIM1 abolish SOCE and cause anhidrosis.
- SOCE controls activation of Ca2+-activated Cl− channels (CaCC).
- CaCC function in human sweat gland cells is mediated by TMEM16A.

Store-operated Ca2+ entry (SOCE) is a conserved mechanism of Ca2+ influx that regulates Ca2+ signaling in many cell types. SOCE is activated by depletion of endoplasmic reticulum (ER) Ca2+ stores in response to physiological agonist stimulation. After it was first postulated by J.W. Putney Jr. in 1986, SOCE has been described in a large number of non-excitable cell types including secretory cells of different exocrine glands. Here we discuss the mechanisms by which SOCE controls salt and fluid secretion in exocrine glands, with a special focus on eccrine sweat glands. In sweat glands, SOCE plays an important, non-redundant role in regulating the function of Ca2+-activated Cl− channels (CaCC), Cl− secretion and sweat production. In the absence of key regulators of SOCE such as the CRAC channel pore subunit ORAI1 and its activator STIM1, the Ca2+-activated chloride channel TMEM16A is inactive and fails to secrete Cl−, resulting in anhidrosis in mice and human patients.

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