[Frontiers in Bioscience 12, 3554-3565, May 1, 2007]

The biosynthesis and processing of neuropeptides: lessons from prothyrotropin releasing hormone (proTRH)

Mario Perello1, Eduardo A. Nillni1,2

1Division of Endocrinology, Department of Medicine, Brown Medical School, Rhode Island Hospital, 2Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI


1. Abstract
2. Introduction
3. ProTRH, a multifunctional protein
4. Biosynthesis of proTRH
5. Enzymes responsible for the processing of proTRH
5.1. Prohormone convertases (PCs)
5.2 Carboxy peptidases (CPs)
5.3. Peptidyl alpha-amidating monooxygenase (PAM)
6. Processing and sorting of proTRH
7. ProTRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN)
8. Regulation of the biosynthesis of proTRH in the PVN
9. Regulation of the processing of proTRH in the PVN
7. Perspective
11. Acknowledgment
12. References


The biosynthesis of prohormone-derived peptides is a complex cellular process, which requires specific cleavage, sorting, and modifications of the peptides before the final generation of the bioactive products. In this review, we describe the current knowledge of the cell biology of a key prohormone: proThyrotropin Releasing Hormone (proTRH), which is the precursor of the TRH peptide. In particular, we focus on the biosynthesis of the hypophysiotropic TRH, which is produced in the hypothalamic paraventricular nucleus (PVN) and is the main activator of the hypothalamic-pituitary-thyroid (HPT) axis. Recently, we showed that the regulation of the biosynthesis of TRH in the PVN also occurs at post-translational level through coordinated changes in proTRH processing, by the action of the prohormone convertase (PC1/3 and PC2) processing enzymes. Such regulation, which represents a novel aspect in the regulation of the neuropeptide biosynthesis, ultimately would lead to a more effective processing of prohormones into mature peptides.