Store-operated cyclic AMP signalling mediated by STIM1

Depletion of Ca²⁺ from the endoplasmic reticulum (ER) results in activation of plasma membrane Ca²⁺ entry channels. This 'store-operated' process requires translocation of a transmembrane ER Ca²⁺ sensor protein, stromal interaction molecule 1 (STIM1), to sites closely apposed to Ca²⁺ channels at the cell surface. However, it is not known whether a reduction in Ca²⁺ stores is coupled to other signalling pathways by this mechanism. We found that lowering the concentration of free Ca²⁺ in the ER, independently of the cytosolic Ca²⁺ 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 Ca²⁺ depletion to adenylyl cyclase activity. We propose the existence of a pathway (store-operated cAMP signalling or SOcAMPS) in which the content of internal Ca²⁺ stores is directly connected to cAMP signalling through a process that involves STIM1.