Physiological Actions and Receptors

Abstract

Prolactin has become highly specialized in mammals to play important roles in reproduction. The core physiological actions of prolactin in mammals are antigonadotropic and pro-lactogenic. These core physiological functions drive the most obvious pathological consequences of excess prolactin secretion (hyperprolactinemia). The few known examples of isolated prolactin deficiency have been characterized by alactogenesis without other discernable consequences. Members of the type 1 cytokine receptor family, which includes the prolactin receptor, share a common overall structure with a single-pass membrane-spanning domain. Activation of the prolactin receptor complex results from conformational changes induced by articulation of a single ligand molecule with binding sites on two receptor molecules. The primary, and maybe exclusive, catalytic participant in normal prolactin receptor signal transduction is the receptor-associated tyrosine kinase JAK2. JAK2 phosphorylates multiple targets including itself, the receptors, and STAT5, creating docking and/or dimerization sites on each molecule. The STAT proteins are latent transcription factors that dimerize and translocate to the nucleus after being tyrosine phosphorylated. The genes that are direct targets for transcriptional activation STAT5 are very incompletely understood, even though binding sites for STAT proteins, collectively referred to as GAS elements, have been mapped in the regulatory regions of a variety of genes in prolactin target tissues. In addition to processes controlled by prolactin target genes that respond directly to activated STAT5, gene products that are induced secondarily control certain essential functions. The most important example of a secondarily mediate function is mammary epithelial proliferation, which is driven indirectly by prolactin via induction of RANK-ligand synthesis.