Correlation between prolactin-receptor interaction, down-regulation of receptors, and stimulation of casein and deoxyribonucleic acid biosynthesis in rabbit mammary gland explants.

Increasing concentrations of PRL were added to culture media of rabbit mammary gland explants. After 24 h of culture, free and total PRL receptors, casein synthesis, casein messenger (m) RNA concentrations and DNA synthesis were estimated. In the PRL concentration range of 0-100 ng/ml, receptors were progressively down-regulated by the hormone, but no occupied desaturable receptors could be detected. At concentrations between 1,000 and 20,000 ng/ml, the PRL receptors were increasingly occupied without being quantitatively down-regulated. There exists a reciprocal correlation between the rate of casein synthesis, casein mRNA concentration, DNA synthesis and the down-regulation of the receptors as a function of PRL concentration. The maximal responses were reached around a PRL concentration of 100 ng/ml. Interestingly, with a large excess of PRL a desensitization process was observed, the responses to the hormone being attenuated. This desensitization was more pronounced for DNA synthesis than for casein synthesis or for casein mRNA accumulation. The data suggest that down-regulation of PRL receptors occurs even at physiological concentrations of PRL. These observations are compatible with the hypothesis that each receptor can generate a limited number of intracellular relays eliciting hormonal action before being irreversibly inactivated and degraded. In addition, high concentrations of PRL induce a refractory state in the mammary gland that is possibly related to a low level of peripheral PRL receptors.