Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function
Axel R. Concepcion, … , David I. Yule, Stefan Feske
Axel R. Concepcion, … , David I. Yule, Stefan Feske
Published October 10, 2016
Citation Information: J Clin Invest. 2016;126(11):4303-4318. https://doi.org/10.1172/JCI89056.
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Research Article Cell biology Dermatology

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

Abstract

Eccrine sweat glands are essential for sweating and thermoregulation in humans. Loss-of-function mutations in the Ca2+ release–activated Ca2+ (CRAC) channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE), and patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures. Here we have shown that CRAC channel–deficient patients and mice with ectodermal tissue–specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development. SOCE was absent in agonist-stimulated sweat glands from Orai1K14Cre and Stim1/2K14Cre mice and human sweat gland cells lacking ORAI1 or STIM1 expression. In Orai1K14Cre mice, abolishment of SOCE was associated with impaired chloride secretion by primary murine sweat glands. In human sweat gland cells, SOCE mediated by ORAI1 was necessary for agonist-induced chloride secretion and activation of the Ca2+-activated chloride channel (CaCC) anoctamin 1 (ANO1, also known as TMEM16A). By contrast, expression of TMEM16A, the water channel aquaporin 5 (AQP5), and other regulators of sweat gland function was normal in the absence of SOCE. Our findings demonstrate that Ca2+ influx via store-operated CRAC channels is essential for CaCC activation, chloride secretion, and sweat production in humans and mice.

Authors

Axel R. Concepcion, Martin Vaeth, Larry E. Wagner II, Miriam Eckstein, Lee Hecht, Jun Yang, David Crottes, Maximilian Seidl, Hyosup P. Shin, Carl Weidinger, Scott Cameron, Stuart E. Turvey, Thomas Issekutz, Isabelle Meyts, Rodrigo S. Lacruz, Mario Cuk, David I. Yule, Stefan Feske

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Figure 1

Sweat glands are present in CRAC channel–deficient patients with EDA-ID.

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Sweat glands are present in CRAC channel–deficient patients with EDA-ID....
(A) H&E staining of eccrine sweat glands in the dermis of a healthy control donor (HD) and a patient with ORAI1 p.R91W loss-of-function mutation at low magnification. (B) Alcian blue staining of the same biopsies shown in A to detect acid mucopolysaccharides in dark cells (green arrowheads). Arrows indicate different cell types in the secretory portion of sweat glands (CC, clear cells; DC, dark cells; and MC, myoepithelial cells). (C) H&E staining of eccrine sweat glands in the dermis of an HD and patients with ORAI1 p.R91W (magnification of boxed area in A), ORAI1 p.V181SfsX8, and STIM1 p.P165Q mutations that abolish SOCE. Asterisks indicate the lumen of secretory sweat glands. Scale bars in A–C: 50 μm. (D) Quantification of sweat gland lumens from human skin biopsies shown in C. Bars represent the means of 3 HDs and 3 individual patients. Between 2 and 4 coiled nests of eccrine sweat glands were analyzed per skin biopsy. Statistical analyses were performed by 1-way ANOVA using HDs as a reference and multiple comparisons. ***P < 0.001.