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

Abstract

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.

Cloning and hypothalamic distribution of the chicken thyrotropin-releasing hormone precursor cDNA

“…1) and mouse, six in human, seven in Xenopus and eight in salmon) and in the amino acid sequences of the so-called 'cryptic peptides' or 'peptide spacers' (Ps), which are set free when preproTRH is proteolytically processed. The search for the biological function of these connecting peptides started years ago and focussed mainly on rat Ps4 or preproTRH-(160-169) (Bulant et al 1990, 1992a, Ladram et al 1992, Carr et al 1993, Pekary 1998 and rat (Liao et al 1988a,b;Roussel et al 1994, Redei et al 1995, McGivern et al 1997 (Fig. 1).…”

Central hypothyroidism

“…[19] The pre-pro-TRH fragment stimulates TSH β gene expression in the pituitary gland, which enhances TRH-induced release of TSH and prolactin (PRL) from the pituitary. [112021] There are two distinct regions of human TSH β gene that respond positively to TRH. This interaction is further dependent on the presence of other factors such as cAMP response element-binding protein (CREB)-binding protein (CBP) and Pit-1, which act synergistically with TRH to stimulate the TSH β gene promoter.…”