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It is well known that Ca<jats:sup>2+<\/jats:sup>-mobilizing agonists also stimulate colonic anion secretion. However, CFTR is apparently not activated directly by Ca<jats:sup>2+<\/jats:sup>, and the existence of apical Ca<jats:sup>2+<\/jats:sup>-dependent Cl<jats:sup>\u2212<\/jats:sup>channels in the native colonic epithelium is controversial, leaving the identity of the Ca<jats:sup>2+<\/jats:sup>-activated component unresolved. We recently showed that decreasing free Ca<jats:sup>2+<\/jats:sup>concentration ([Ca<jats:sup>2+<\/jats:sup>]) within the endoplasmic reticulum (ER) lumen elicits a rise in intracellular cAMP. This process, which we termed \u201cstore-operated cAMP signaling\u201d (SOcAMPS), requires the luminal ER Ca<jats:sup>2+<\/jats:sup>sensor STIM1 and does not depend on changes in cytosolic Ca<jats:sup>2+<\/jats:sup>. Here we assessed the degree to which SOcAMPS participates in Ca<jats:sup>2+<\/jats:sup>-activated Cl<jats:sup>\u2212<\/jats:sup>transport as measured by transepithelial short-circuit current ( I<jats:sub>sc<\/jats:sub>) in polarized T84 monolayers in parallel with imaging of cAMP and PKA activity using fluorescence resonance energy transfer (FRET)-based reporters in single cells. In Ca<jats:sup>2+<\/jats:sup>-free conditions, the Ca<jats:sup>2+<\/jats:sup>-releasing agonist carbachol and Ca<jats:sup>2+<\/jats:sup>ionophore increased I<jats:sub>sc<\/jats:sub>, cAMP, and PKA activity. These responses persisted in cells loaded with the Ca<jats:sup>2+<\/jats:sup>chelator BAPTA-AM. The effect on I<jats:sub>sc<\/jats:sub>was enhanced in the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), inhibited by the CFTR inhibitor CFTR<jats:sub>inh<\/jats:sub>-172 and the PKA inhibitor H-89, and unaffected by Ba<jats:sup>2+<\/jats:sup>or flufenamic acid. We propose that a discrete component of the \u201cCa<jats:sup>2+<\/jats:sup>-dependent\u201d secretory activity in the colon derives from cAMP generated through SOcAMPS. This alternative mode of cAMP production could contribute to the actions of diverse xenobiotic agents that disrupt ER Ca<jats:sup>2+<\/jats:sup>homeostasis, leading to diarrhea.<\/jats:p>","DOI":"10.1152\/ajpgi.00214.2015","type":"journal-article","created":{"date-parts":[[2015,8,28]],"date-time":"2015-08-28T02:19:48Z","timestamp":1440728388000},"page":"G670-G679","source":"Crossref","is-referenced-by-count":12,"title":["\u201cStore-operated\u201d cAMP signaling contributes to Ca<sup>2+<\/sup>-activated Cl<sup>\u2212<\/sup>secretion in T84 colonic cells"],"prefix":"10.1152","volume":"309","author":[{"given":"Jonathan M.","family":"Nichols","sequence":"first","affiliation":[{"name":"Department of Veterans Affairs Boston Healthcare System and Department of Surgery, Brigham &amp; Women's Hospital and Harvard Medical School, West Roxbury, 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