Abstract
Store-operated Ca2+ entry (SOCE) provides local and global Ca2+ signals that regulate numerous cellular functions. The stromal interaction proteins STIMs) reside within the ER and function as sensors of the ER-[Ca2+]. STIM1 and STIM2 share a high sequence identity and yet, both have different functions in the store-operated calcium entry (SOCE) pathway. Following ER-Ca2+ store depletion STIM1 aggregates and translocates to the ER-plasma membrane (ER-PM) junctional regions where it binds to and gates plasma membrane Orai1. STIM2 also clusters in response to stimulation but is a relatively weak activator of Orai1. In the present study, we investigated the role of STIM2 in SOCE and show that loss of STIM2 decreases the sensitivity of SOCE activation by the agonist. Knock down of endogenous STIM2 did not affect CCh-induced intracellular Ca2+ release but changed the pattern [Ca2+]i signals due to SOCE. Sustained elevations in cells were changed to an oscillatory pattern with loss of STIM2 whereas SOCE-dependent [Ca2+]i signals were abolished with STIM1 knock down. Further, STIM2 was required for clustering STIM1 in ER-PM junctional domains at physiological [CCh], where there is relative less depletion of internal Ca2+ stores. Further analysis revealed critical regions in STIM2 that determine its interaction with STIM1 and attenuate agonist-activation of SOCE. Together, our data demonstrate that STIM2 has a critical role in SOCE and agonist-stimulated Ca2+ signaling, as it escorts STIM1 to the ER-PM junctional domains where STIM1-Orai1 channels are assembled.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call