Interactions Between Secretory Pathway Ca2+-ATPase 2 with TRP and Orai Channels Mediate Store Independent Ca2+ Entry in Lactation

Abstract

Secretory pathway Ca2+ ATPases (SPCAs) are important in sequestering Ca2+ and Mn2+ from the cytoplasm into the Golgi and post-Golgi vesicles for important post-translational modifications to a multitude of enzymes. The two isoforms, SPCA1 and SPCA2 share high homology but have distinct localization and distribution. Whereas SPCA1 is a ubiquitous and essential protein with conventional Golgi localization, SPCA2 is expressed in highly secretory or absorptive epithelia where it can traffic to the plasma membrane. We showed that SPCA2 interacts with Orai1 to activate store-independent Ca2+ entry in breast cancer (Feng, et al, 2010). However, the normal physiological explanation for these interactions remains to be elucidated. Clinical studies have suggested a possible preventive role for lactation with respect to breast cancer (Neubauer, et al, 1994). In this study, we examine the interaction of SPCA2 with Orai1 and TRP channels throughout lactation. We show that: i) SPCA2 interacts with Orai1 and TRP channels, ii) these interactions are involved in the early stages of lactation and iii) these interactions may play a role in the sequestration of Ca2+ from the blood (2mM Ca2+ ) to the milk (40-80mM Ca2+).