Role of calcium in the pathway for milk protein secretion and possible relevance for mammary gland physiology.

In an attempt to define control points within the secretory pathway for casein synthesis and secretion, we have examined the role of both cytosolic and intra-organelle Ca2+ in the control of casein synthesis, phosphorylation and secretion. In addition, the possible role of cell volume changes in stretch-activation of Ca2+ signals was examined. Examination of the kinetics of casein secretion from freshly isolated lactating mouse mammary acini showed that a portion of the newly synthesized casein was secreted in a constitutive manner. A further portion remained within the cells, and this was released following elevation of the intracellular free calcium concentration ([Ca2+]i) using ionomycin, indicating the presence of a Ca(2+)-regulated pathway for casein release. An increase in [Ca2+]i occurred in response to hypotonic challenge to induce cell swelling, and this involved both Ca2+ entry and Ca2+ mobilization from intracellular stores. Experiments examining the effects of depletion of intra-organelle Ca2+ indicated that intra-organelle Ca2+ was required for maintained casein phosphorylation, but not its secretion. Depletion of Ca2+ from the endoplasmic reticulum led to a marked inhibition of casein synthesis. The possible significance of these control mechanisms for the physiology of the mammary gland is discussed.