title: A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland.
abstract: Activation of an apical Ca(2+)-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(-/-)). Ca(2+)-dependent salivation was abolished in Tmem16A(-/-) mice, demonstrating that Tmem16A is obligatory for Ca(2+)-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A(-/-) mice in response to the β-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(∆F508/∆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 β-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, Ca(2+)-dependent fluid secretion in adult mouse salivary glands.
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; marcelo.catalan@nih.gov james.melvin@nih.gov.
authors: Marcelo A
authors: http://orcid.org/0000-0003-3544-2821
authors: MA
authors: Catalán
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan;
authors: Yusuke
authors: Y
authors: Kondo
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors: Gaspar
authors: G
authors: Peña-Munzenmayer
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors: Yasna
authors: Y
authors: Jaramillo
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors: Frances
authors: F
authors: Liu
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors: Sooji
authors: S
authors: Choi
authors: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, CA 90033; and.
authors: Edward
authors: E
authors: Crandall
authors: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, CA 90033; and.
authors: Zea
authors: Z
authors: Borok
authors: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, CA 90033; and.
authors: Per
authors: P
authors: Flodby
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
authors: Gary E
authors: GE
authors: Shull
authors: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; marcelo.catalan@nih.gov james.melvin@nih.gov.
authors: James E
authors: JE
authors: Melvin
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000818:Animals; D000075369:Anoctamin-1; D018118:Chloride Channels / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012463:Saliva / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism*
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D011943:Receptors, Adrenergic, beta
keywords: Cftr channel; Cl− channel; Tmem16A/Ano1; acinar cell; secretion
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