Key result
CaMKIIδ overexpression enhances STIM1-Orai1 interaction and store-operated Ca2+ entry.
Why the study?
CaMKII is a regulator of store-operated Ca2+ entry (SOCE), but the mechanism by which CaMKII regulates SOCE remains obscure.
CaMKII up-regulates store-operated Ca2+ entry by increasing STIM1 aggregation and interaction with Orai1, providing insight into potential pathological mechanisms.
May inform CaMKII-SOCE links in pathology models; leaves open validation in cardiovascular tissues before any clinical consideration.
BACKGROUND/AIMS: Upon Ca2+ store depletion, stromal interaction molecule 1 (STIM1) oligomerizes, redistributes near plasmalemma to interact with Ca2+ selective channel-forming subunit (Orai1) and initiates store-operated Ca2+ entry (SOCE). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a regulator of SOCE, but how CaMKII regulates SOCE remains obscure. METHODS: Using Fura2, confocal microscopy, co-immunoprecipitation, specific blocker and overexpression/knockdown approaches, we evaluated STIM1 aggregation and its interaction with Orai1, and SOCE upon Ca2+ store depletion in thapsigargin (TG) treated HEK293 and HeLa cells. RESULTS: Overexpression of CaMKIIδ enhanced TG-induced STIM1 co-localization and interaction with Orai1 as well as SOCE. In contrast, CaMKIIδ knockdown and a specific inhibitor of CaMKII suppressed them. In addition, overexpression or knockdown of CaMKIIδ in TG treated cells exhibited increased or reduced STIM1 clustering and plasmalemma redistribution, respectively. CONCLUSION: CaMKII up-regulates SOCE by increasing STIM1 aggregation and interaction with Orai1. This study provides an additional insight into SOCE regulation and a potential mechanism for CaMKII involvement in some pathological situations through crosstalk with SOCE.
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Li et al. (2018) studied this question. CaMKIIδ overexpression, knockdown, or inhibition was evaluated on STIM1 aggregation, interaction with Orai1, and SOCE upon Ca2+ store depletion. Overexpression of CaMKIIδ enhanced thapsigargin-induced STIM1 co-localization and interaction with Orai1 as well as store-operated Ca2+ entry, whereas its knockdown or inhibition suppressed them.
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