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

•Novel data confirm that SPCA2/Orai1 binding triggers store-independent Ca2+ entry.•SPCA2 directly couples Orai1 Ca2+ influx to Ca2+ uptake in the secretory pathway.•The SPCA2 C-terminus is essential for Orai1 activation and SPCA2 activity.•The SPCA2 N-terminus is dispensable for Orai1 activation, but not SPCA2 activity.•The SPCA2 N-terminus determines SICE, stability, targeting and transport activity.

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.

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