期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 7, 页码 2263-2268出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415739112
关键词
acinar cell; secretion; Cl- channel; Tmem16A/Ano1; Cftr channel
资金
- Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH)
- Hastings Foundation
- Whittier Foundation
- NIH [DK050594]
Activation of an apical Ca2+-activated Cl- channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCC-mediated Cl- current and Cl- efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl- channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A(-/-)). Ca2+-dependent salivation was abolished in Tmem16A(-/-) mice, demonstrating that Tmem16A is obligatory for Ca2+-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A(-/-) mice in response to the beta-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr(Delta F508/Delta F508)) or ClC-2 (Clcn2(-/-)) Cl- channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl- channel. Indeed, Cl- channel blockers abolished fluid secretion, indicating that Cl(-)channel activity is critical for IPR-stimulated secretion. These data suggest that beta-adrenergic-induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A(-/-) mice identify Tmem16A as the Cl- channel essential for muscarinic, Ca2+-dependent fluid secretion in adult mouse salivary glands.
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