Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle.
نویسندگان
چکیده
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca2+ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca2+ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca2+-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.
منابع مشابه
Secretory state regulates Zn2+ transport in gastric parietal cell of the rabbit.
Secretory compartments of neurons, endocrine cells, and exocrine glands are acidic and contain high levels of labile Zn2+. Previously, we reported evidence that acidity is regulated, in part, by the content of Zn2+ in the secretory [i.e., tubulovesicle (TV)] compartment of the acid-secreting gastric parietal cell. Here we report studies focusing on the mechanisms of Zn2+ transport by the TV com...
متن کاملCalcium signaling mechanisms in the gastric parietal cell.
Gastric hydrochloric acid (HCl) secretion is stimulated in vivo by histamine, acetylcholine, and gastrin. In vitro studies have shown that histamine acts mainly via a cAMP-dependent pathway, and acetylcholine acts via a calcium-dependent pathway. Histamine also elevates intracellular calcium ([Ca2+]i) in parietal cells. Both gastrin and acetylcholine release histamine from histamine-containing ...
متن کاملAspirin potentiates prestimulated acid secretion and mobilizes intracellular calcium in rabbit parietal cells.
The effects of aspirin on gastric acid secretion were studied in isolated rabbit parietal cells (PC). Aspirin (10(-5) M) potentiated histamine-, dibutyryl cyclic AMP (dbcAMP)-, forskolin- and 3-isobutyl-1-methylxanthine-stimulated acid secretion without affecting basal acid secretion. Augmentation of secretagogue-stimulated acid secretion by aspirin was dependent on calcium (Ca2+) since potenti...
متن کاملیافته های تازه درباره سلولهای پاریتال معده
During the last five years the recognition of ionic channels in the parietal cells of stomach and acid chloride mechanisms of secretion by these cells has become totally clear by the "Patch Oamp" technique. The apical cytoplasm in the oxyntic cells are in the form of vesicles where membranes contain H+, K+ -ATPase pump. Stimulation causes fusion of these tubular vesicles with the cell membran o...
متن کاملSecretory state regulates Zn transport in gastric parietal cell of the rabbit
Naik HB, Beshire M, Walsh BM, Liu J, Soybel DI. Secretory state regulates Zn transport in gastric parietal cell of the rabbit. Am J Physiol Cell Physiol 297: C979–C989, 2009. First published August 12, 2009; doi:10.1152/ajpcell.00577.2008.—Secretory compartments of neurons, endocrine cells, and exocrine glands are acidic and contain high levels of labile Zn . Previously, we reported evidence th...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Developmental cell
دوره 41 3 شماره
صفحات -
تاریخ انتشار 2017