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Depletion of Ca(2+) from the endoplasmic reticulum (ER) results in activation of plasma membrane Ca(2+) entry channels. This 'store-operated' process requires translocation of a transmembrane ER Ca(2+) sensor protein, stromal interaction molecule 1 (STIM1), to sites closely apposed to Ca(2+) channels at the cell surface. However, it is not known whether a reduction in Ca(2+) stores is coupled to other signalling pathways by this mechanism. We found that lowering the concentration of free Ca(2+) in the ER, independently of the cytosolic Ca(2+) concentration, also led to recruitment of adenylyl cyclases. This resulted in enhanced cAMP accumulation and PKA activation, measured using FRET-based cAMP indicators. Translocation of STIM1 was required for efficient coupling of ER Ca(2+) depletion to adenylyl cyclase activity. We propose the existence of a pathway (store-operated cAMP signalling or SOcAMPS) in which the content of internal Ca(2+) stores is directly connected to cAMP signalling through a process that involves STIM1.

Original publication




Journal article


Nat Cell Biol

Publication Date





433 - 442


Adenylyl Cyclases, Calcium, Calcium Signaling, Cell Line, Chelating Agents, Cyclic AMP, Cytosol, Endoplasmic Reticulum, Enzyme Activation, Extracellular Space, Humans, Intracellular Space, Membrane Proteins, Neoplasm Proteins, Phosphoric Diester Hydrolases, Protein Transport, Stromal Interaction Molecule 1