Store-operated cyclic AMP signalling mediated by STIM1

Konstantinos Lefkimmiatis, Meera Srikanthan, Isabella Maiellaro, Mary Pat Moyer, Silvana Curci, Aldebaran M. Hofer

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)433-442
Number of pages10
JournalNature Cell Biology
Volume11
Issue number4
DOIs
StatePublished - 2009
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to the following individuals for their kind gifts of plasmids: Kees Jalink for the Epac sensor, Roger Tsien for mCherry, Jin Zhang for AKAR3, Marie Dziadek and Lorna Johnstone for STIM1 and STIM2, Masaru Okabe for pCX–EGFP, and Tobias Meyer for YFP–STIM1, YFP–STIM1D76A, and YFP–STIM2 constructs. We thank Jessica Roy for technical assistance and Drs. Dheeraj Pelluru, Eberhard Frömter and Raj K. Goyal for helpful comments. This study was supported by a Merit Review award from the Department of Veteran’s Affairs (A.M.H.) and by an NIH Center grant from the Harvard Digestive Diseases Center (to A.M.H.). K.L. is the recipient of an American Heart Association Postdoctoral Fellowship award..

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