Is Ps4 (prepro-TRH [160-169]) More Than an Enhancer for Thyrotropin-Releasing Hormone?

Ps4 (thyrotropin-releasing hormone [TRH]-enhancing peptide), one of the cryptic peptides resulting from the proteolytic processing of prepro-TRH to produce TRH, has a growing list of functions in addition to its well-established ability to enhance the TRH-induced release of thyrotropin (TSH) and prolactin from the pituitary. Intramedullary coadministration of Ps4 and TRH increased gastric acid secretion above the level produced by TRH alone and intracisternal infusion of Ps4 resulted in a substantial reduction in the levels of prepro-TRH-derived peptide levels in the rat pituitary, including Ps4. High-affinity receptors for Ps4 are widely distributed. In addition to the very high Ps4 binding capacity of the folliculo-stellate cells of the anterior pituitary, abundant Ps4 receptors are found in the urinary bladder, vas deferens, central nervous system, reproductive tissues, and pancreas. Targeted prepro-TRH gene disruption results in hyperglycemia as well as the expected hypothyroidism. The observed disregulation of thyroid and glucose homeostasis in the TRH "knockout" mouse clearly demonstrates that prepro-TRH-derived peptides and their cognate receptors within the pituitary, pancreas, and other neural and endocrine systems are of fundamental importance to a variety of physiological systems and merit structural and functional characterization.