{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T21:55:26Z","timestamp":1771538126944,"version":"3.50.1"},"reference-count":43,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2008,9]]},"abstract":"<jats:p> We previously found that the phosphorylation of ERK1\/2 by submaximal concentrations of the muscarinic receptor ligand carbachol was potentiated in rat parotid acinar cells exposed to ouabain, a cardiac glycoside that inhibits the Na-K-ATPase. We now report that this signaling phenomenon involves the prevention of negative regulation of extracellular signal-regulated kinase-1\/2 (ERK1\/2) that is normally mediated by AMP-activated protein kinase (AMPK). Carbachol increases the turnover of the ATP-consuming Na-K-ATPase, reducing intracellular ATP and promoting the phosphorylation\/activation of the energy sensor AMPK. Ouabain blocks the reduction in ATP and subsequent AMPK phosphorylation, which is regulated by the AMP-to-ATP ratio. The ouabain-promoted enhancement of ERK1\/2 phosphorylation was not reproduced in Par-C10 cells, an immortalized rat parotid cell line that did not respond to carbachol with an ATP reduction and that employs an upstream AMPK kinase (Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase kinase, CaMKK) different from that (LKB1) in native cells. In native parotid cells, inhibitory effects of AMPK on ERK1\/2 signaling were examined by activating AMPK with 5-aminoimidazole-4-carboxamide-1-\u03b2-d-ribofuranoside (AICAR), which is converted to an AMP mimetic but does not alter parotid ATP levels. AICAR-treated cells display increases in AMPK phosphorylation and a reduced phosphorylation of ERK1\/2 subsequent to activation of muscarinic and P2X<jats:sub>7<\/jats:sub> receptors, which promote increases in Na-K-ATPase turnover, but not upon epidermal growth factor receptor activation. These results suggest that carbachol-initiated AMPK activation can produce a negative feedback on ERK1\/2 signaling in response to submaximal muscarinic receptor activation and that increases in fluid secretion can modulate receptor-initiated signaling events indirectly by producing ion transport-dependent decreases in ATP. <\/jats:p>","DOI":"10.1152\/ajpcell.00140.2008","type":"journal-article","created":{"date-parts":[[2008,7,17]],"date-time":"2008-07-17T01:40:23Z","timestamp":1216258823000},"page":"C590-C599","source":"Crossref","is-referenced-by-count":23,"title":["Regulation of ERK1\/2 by ouabain and Na-K-ATPase-dependent energy utilization and AMPK activation in parotid acinar cells"],"prefix":"10.1152","volume":"295","author":[{"given":"Stephen P.","family":"Soltoff","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee","family":"Hedden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Aizman O, Uhlen P, Lal M, Brismar H, Aperia A. 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