Secretory pathway Ca-ATPase 2 (SPCA2) gene knockout results in mouse mammary gland changes and a secretory defect

Abstract Calcium influx into the basolateral mammary cell is thought to be due partly to an unconventional partnering of SPCA2 and the calcium channel protein ORAI1 in vitro. ORAI1’s role in mammary secretory cell calcium influx, in support of milk calcium, has been confirmed in ORAI1 knockout (KO) mice. We examine the role of SPCA2 on mammary cell calcium influx in support of milk calcium concentration in SPCA2 KO mice. The SPCA2 KO resulted in a significant 40% reduction in milk calcium and a 57% reduction in milk manganese concentrations. The loss of SPCA2 was associated with a significant 55% increase in SPCA1, which may be compensatory. The expression of other calcium transporters/channels such as PMCA2/NHERF1, ORAI1, NCX1, and TMEM165 were not affected by the loss of SPCA2. Histologically SPCA2 KO mammary glands showed increased adiposity and altered structure. Milk production was significantly down in SPCA2 KO mice, but milk fat, protein, and lactose were unaffected. The significant decline in milk calcium in SPCA2 KO mice indirectly supports the SPCA2 role as an ORAI1 partner in calcium influx into mammary tissue. Further, studies will be required to clarify this relationship between SPCA2, ORAI1, and STIM1 on mammary calcium influx in vivo.