Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 16, Issue 11, Pages 2715-2725Publisher
WILEY
DOI: 10.1111/j.1582-4934.2012.01592.x
Keywords
calcium; cyclic AMP; endoplasmic reticulum
Categories
Funding
- Harvard Digestive Diseases Center [5P30DK034854-24]
- NIDDK [1R21DK088197-01]
- Medical Research Service of the Veteran's Administration [VA-ORD 1 I01 BX000968-01]
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Diverse pathophysiological processes (e.g. obesity, lifespan determination, addiction and male fertility) have been linked to the expression of specific isoforms of the adenylyl cyclases (AC1-AC10), the enzymes that generate cyclic AMP (cAMP). Our laboratory recently discovered a new mode of cAMP production, prominent in certain cell types, that is stimulated by any manoeuvre causing reduction of free [Ca2+] within the lumen of the endoplasmic reticulum (ER) calcium store. Activation of this store-operated pathway requires the ER Ca2+ sensor, STIM1, but the identity of the enzymes responsible for cAMP production and how this process is regulated is unknown. Here, we used sensitive FRET-based sensors for cAMP in single cells combined with silencing and overexpression approaches to show that store-operated cAMP production occurred preferentially via the isoform AC3 in NCM460 colonic epithelial cells. Ca2+ entry via the plasma membrane Ca2+ channel, Orai1, suppressed cAMP production, independent of store refilling. These findings are an important first step towards defining the functional significance and to identify the protein composition of this novel Ca2+/cAMP crosstalk system.
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