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An unconventional interaction between SPCA2, an isoform of the Golgi secretory pathway Ca 2+ -ATPase, and the Ca 2+  influx channel Orai1, has previously been shown to contribute to elevated Ca 2+  influx in breast cancer derived cells. In order to investigate the physiological role of this interaction, we examined expression and localization of SPCA2 and Orai1 in mouse lactating mammary glands. We observed co-induction and co-immunoprecipitation of both proteins, and isoform-specific differences in the localization of SPCA1 and SPCA2. Three-dimensional cultures of normal mouse mammary epithelial cells were established using lactogenic hormones and basement membrane. The mammospheres displayed elevated Ca 2+  influx by store independent mechanisms, consistent with upregulation of both SPCA2 and Orai1. Knockdown of either SPCA2 or Orai1 severely depleted Ca 2+  influx and interfered with mammosphere differentiation. We show that SPCA2 is required for plasma membrane trafficking of Orai1 in mouse mammary epithelial cells and that this function can be replaced, at least in part, by a membrane-anchored C-terminal domain of SPCA2. These findings clearly show that SPCA2 and Orai1 function together to regulate Store-independent Ca 2+  entry (SICE), which mediates the massive basolateral Ca 2+  influx into mammary epithelia to support the large calcium transport requirements for milk secretion.

SPCA2 Regulates Orai1 Trafficking and Store Independent Ca2+ Entry in a Model of Lactation