NIH Research Festival
Regulated exocytosis is a fundamental polarized cellular activity that orchestrates the release of neurotransmitters and exocrine glands secretory granules (Zymogens) at the apical pole in response to a stimulus. Phospholipids have established roles in membranes trafficking, with PtdSer externalization has roles in cell-cell fusion, synaptic exocytosis and endocytosis, and in several cell death modalities and viral entry. However, the role and mechanisms of PtdSer regulation, particularly in epithelial exocytosis and epithelial fluid and electrolyte secretion, are not well understood. We discovered that both activities of TMEM16F (ANO6), Ca2+ activated Cl- channel function and PtdSer scrambling are required epithelial fluid and electrolyte secretion and for regulated exocytosis, respectively. Exocytosis by pancreatic acinar cells is triggered by Ca2+, whereas exocytosis by salivary glands acinar cells is primarily mediated by cAMP but Ca2+ and cAMP synergize to mediate the physiological response. Exocytosis and fluid secretion by the Pancreas and Salivary Gland are markedly reduced in ANO6-/- mice, which we traced to impaired receptor stimulated PtdSer scrambling and Cl- channel function by ANO6 in isolated acinar cells, respectively. Impaired exocytosis occurred in the face of minimally altered receptor stimulated second messenger generation and likely involved both second messenger detection by the exocytotic apparatus. Impaired fluid secretion is being traced to the role of ANO6 in the synergistic cAMP/Ca2+ component of fluid secretion.
Scientific Focus Area: Cell Biology
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