Store-operated cyclic AMP signalling mediated by STIM1.
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.
Lefkimmiatis
Konstantinos
K
VA Boston Healthcare System and the Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, West Roxbury, Massachusetts 02132, USA.
Srikanthan
Meera
M
Maiellaro
Isabella
I
Moyer
Mary Pat
MP
Curci
Silvana
S
Hofer
Aldebaran M
AM
D000262:Adenylyl Cyclases / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1
D002614:Chelating Agents; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D002118:Calcium