Mammary gland ion transport is essential for lactation and is regulated by prolactin and glucocorticoids. This study delineates the roles of prolactin receptors (PRLR) and long-term prolactin and dexamethasone (P-D)-mediation of [Ca2+]i and Cl？ transport in HC-11 cells. P-D (24？h) suppressed ATP-induced [Ca2+]i. This may be due to decreased Ca2+ entry since P-D decreased transient receptor potential channel 3 (TRPC3) but not secretory pathway Ca2+-ATPase 2 (SPCA2) mRNA. ATP increased Cl？ transport, measured by iodide (I？) efflux, in control and P-D-treated cells. P-D enhanced I？ efflux response to cAMP secretagogues without altering Cl？ channels or NKCC cotransporter expression. HC-11 cells contain only the long form of PRLR (PRLR-L). Since the short isoform, PRLR-S, is mammopoietic, we determined if transfecting PRLR-S (rs) altered PRLR-L-mediated Ca2+ and Cl？ transport. Untreated rs cells showed an attenuated [Ca2+]i response to ATP with no further response to P-D, in contrast to vector-transfected (vtc) controls. P-D inhibited TRPC3 in rs and vtc cells but increased SPCA2 only in rs cells. As in wild-type, cAMP-stimulated Cl？ transport, in P-D-treated vtc and rs cells. In summary, 24？h P-D acts via PRLR-L to attenuate ATP-induced [Ca2+]i and increase cAMP-activated Cl？ transport. PRLR-S fine-tunes these responses underscoring its mammopoietic action. 1. Introduction Prolactin is critical for the development of the mammary gland into a secretory type gland during lactation. Either acting alone or in concert with other hormones, prolactin has a plethora of effects on mammary epithelial function during lactation. Amongst other functions prolactin stimulates the production and/or secretion of casein, lipid [1], amino acids [2], and lactose [3] and activates ion transport processes such as those of sodium (Na+), chloride ( C l ？ ), iodide ( I ？ ), and calcium (Ca2+) [4–6]. An increase in intracellular Ca2+ ([Ca2+]i) in the mammary epithelium can serve two functions—it can contribute to the increased Ca2+ content of milk seen during lactation and it can serve as a signaling molecule to stimulate cell function, including fluid, that is, C l ？ secretion, necessary for milk production. Although many studies describe the effect of prolactin on Ca2+ or on fluid transport, there are few studies linking these effects to the two roles of Ca2+. Furthermore the studies are often performed in different animal or cell model systems making inferences difficult. The present study attempts to delineate interplay between hormonal mediation of Ca2+ transporters and fluid
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