SPCA2 couples Ca²⁺ influx via Orai1 to Ca²⁺ uptake into the Golgi/secretory pathway

Dysregulation of the Golgi/Secretory Pathway Ca²⁺ transport ATPase SPCA2 is implicated in breast cancer. During lactation and in luminal breast cancer types, SPCA2 interacts with the plasma membrane Ca²⁺ channel Orai1, promoting constitutive Ca²⁺ influx, which is termed store independent Ca²⁺ entry (SICE). The mechanism of SPCA2/Orai1 interaction depends on the N- and C-termini of SPCA2. These extensions may play a dual role in activating not only Orai1, but also Ca²⁺ transport into the Golgi/secretory pathway, which we tested by investigating the impact of various SPCA2 N- and/or C-terminal truncations on SICE and Ca²⁺ transport activity of SPCA2. C-terminal truncations impair SICE and SPCA2 activity, but also affect targeting, whereas N-terminal truncations affect targeting and inactivate SPCA2, but remarkably, SICE activation remains unaffected. Importantly, overexpression of SPCA2 increases the Ca²⁺ content of non-ER stores, which depends on Orai1 and SPCA2 activity. Thus, Orai1-mediated Ca²⁺-influx and SPCA2-mediated Ca²⁺ uptake activity into the Golgi/secretory pathway might be coupled possibly in a microdomain. This channel/pump complex may efficiently transfer Ca²⁺ into the secretory pathway, which might play a role in SPCA2-expressing secretory cells, such as mammary gland during lactation.