Null Mutation in the Gene Encoding Plasma Membrane Ca2+-ATPase Isoform 2 Impairs Calcium Transport into Milk
Journal of Biological Chemistry
The means by which calcium is transported into the milk produced by mammary glands is a poorly understood process. One hypothesis is that it occurs during exocytosis of secretory products via the Golgi pathway, consistent with the observation that the SPCA1 Ca 2؉ -ATPase, which is expressed in the Golgi, is induced in lactating mammary tissue. However, massive up-regulation of the PMCA2bw plasma membrane Ca 2؉ -ATPase also occurs during lactation and is more strongly correlated with increases
... ed with increases in milk calcium, suggesting that calcium may be secreted directly via this pump. To examine the physiological role of PMCA2bw in lactation we compared lactating PMCA2-null mice to heterozygous and wild-type mice. Relative expression levels of individual milk proteins were unaffected by genotype. However, milk from PMCA2-null mice had 60% less calcium than milk from heterozygous and wild-type mice, the total milk protein concentration was lower, and an indirect measure of milk production (litter weights) suggested that the PMCA2-null mice produce significantly less milk. In contrast, lactose was higher in milk from PMCA2-null mice during early lactation, but by day 12 of lactation there were no differences in milk lactose between the three genotypes. These data demonstrate that the activity of PMCA2bw is required for secretion of much of the calcium in milk. This major secretory function represents a novel biological role for the plasma membrane Ca 2؉ -ATPases, which are generally regarded as premier regulators of intracellular Ca 2؉ . . 1 The abbreviations used are: PMCA, plasma membrane Ca 2ϩ -ATPase; SPCA, secretory pathway Ca 2ϩ -ATPase; SERCA, sarcoplasmic-endoplasmic reticulum Ca 2ϩ -ATPase; Pmca2 ϩ/ϩ , wild type mice; Pmca2 ϩ/Ϫ , heterozygous mice; Pmca2 Ϫ/Ϫ , homozygous mutant mice. 2 The number following PMCA refers to the specific isoform. The first lowercase letter following the number refers to the splice site C splice form, and the next lowercase letter refers to the splice site A splice form.