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

Abstract

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.

CRAC channels in dental enamel cells

“…Patients with mutations in STIM1 and ORAI1 have been described as presenting with ectodermal dysplasia (ED), given that they show phenotypes that are similar to those in ED patients [6–8, 56, 57]. ED are a group of heterogeneous, heritable conditions associated with the abnormal development of ectoderm-derived structures and associated appendages [58].…”

“…The impact of CRAC channel deficiency is, however, critical for the normal function of the developed tissues. Eccrine sweat glands rely on Ca 2+ modulations via ORAI1 to stimulate chloride channels necessary for fluid secretion [56], whereas STIM1 (and its homolog STIM2) are necessary to enable sustainable levels of Ca 2+ transport in ameloblasts to cause proper enamel mineralization [11]. Moreover, patients with mutations in STIM1 or ORAI1 do not always show signs of ED, as some patients showed obvious enamel defects but hairs or nails were normal (e.g.…”

Lipids at membrane contact sites: cell signaling and ion transport

“…Many channels and transporters have been localized to caveolae and plasma membrane raft domains . The Ca 2+ ‐activated Cl − channel ANO1 is activated by localized Ca 2+ signals generated by IP 3 ‐mediated Ca 2+ release and Ca 2+ influx through Orai1 . Unlike Kv2.1, most channels and transporters do not function as tethers.…”

Enamel: Molecular identity of its transepithelial ion transport system

“…SOCE is a common mechanism for the uptake of extracellular Ca 2+ in response to receptor stimulation, generation of the IP3 and release of endoplasmic reticulum (ER) Ca 2+ stores via the IP 3 receptors [42]. SOCE is mediated by the Ca 2+ release activated Ca 2+ (CRAC) channels [43]. The molecular components of CRAC channels are the ER Ca 2+ sensor stromal interaction molecule 1 (STIM1) and STIM2, and the plasma membrane pore subunit of the CRAC channel known as ORAI1 [44, 45].…”