Neuroregulation of proTRH biosynthesis and processing

Abstract

This review presents an overview of the current knowledge on proTRH biosynthesis, its processing, its tissue distribution, and the role of known processing enzymes in proTRH maturation. The neuroendocrine regulation of TRH biosynthesis, the biological actions of its products, and the signal transduction and catabolic pathways used by those products are also reviewed. The widespread expression of proTRH, PC1, and PC2 rnRNAs in hypophysiotropic and extrahypophysiotropic areas of the brain, with their overlapping distribution in many areas, indicates the striking versatility provided by tissue-specific processing in generating quantitative and qualitative differences in nonTRH peptide products as well as TRH. Evidence is presented suggesting that differential processing for proTRH at the intracellular level is physiologically relevant. It is clear that control over the diverse range of proTRH-derived peptides within a specific cell is accomplished most from the regulation at the posttranslational level rather than the translational or transcriptional levels. Several examples supporting this hypothesis are presented in this review. A better understanding of proTRH-derived peptides role represents an exciting new frontier in proTRH research. These connecting sequences in between TRH molecules to form the precursor protein may function as structural or targeting elements that guide the folding and sorting of proTRH and its larger intermediates so that subsequent processing and secretion are properly regulated. The particular anatomical distribution of the proTRH end products, as well as regulation of their levels by neuroendocrine or pharmacological manipulations, supports a unique potential biologic role for these peptides.

Glutaminyl Cyclase Knock-out Mice Exhibit Slight Hypothyroidism but No Hypogonadism

“…Other studies gave rise to the assumption that most of the substrates of QC and isoQC appear to be secreted in their mature form (i.e. containing the pGlu residue at the N terminus) (29,34,35). An extracellular activity of QC might be, therefore, not important for the general maturation process.…”

α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

“…This antiserum has been characterized by Nillni (2000) and shown by electrophoretic separation of immunoprecipitated radiolabeled peptides from rat hypothalamic neurons in culture to recognize a 2.6 kDa peptide characteristic of prepro-TRH 178 -199. After washing in PBS, the tissue sections were incubated in donkey anti-rabbit IgG (1:500; Jackson ImmunoResearch) and the ABC Elite complex (1:100).…”

Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin

“…In subsequent steps, the 15-kDa N-terminal intermediate moiety of proTRH is processed to a 9.5-kDa peptide followed a continuous processing until the end products are generated in secretory granules. It is proposed that the processing of the remaining 10-kDa C-terminal fragment produces the 5.4-kDa C-terminal peptide preproTRH 208 -255 early in the secretory pathway (64), and the remaining intermediate form is further processed to end products in secretory granules (65)(66)(67)(68). Only two sites, thus far, have been identified to be processed by PC2.…”