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Posttranslational Processing of Progrowth Hormone-Releasing Hormone¹

Division of Endocrinology, Department of Medicine, Brown University School of Medicine, Rhode Island Hospital (E.A.N.), Providence, Rhode Island 02903; and the Section of Pediatric Endocrinology and Diabetology, The Herman B. Wells Center for Pediatric Research, Departments of Pediatrics and Physiology, James Whitcomb Riley Hospital for Children, Indiana University (R.S., O.H.P.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Eduardo A. Nillni, Division of Endocrinology, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903.

The prepro-GH-releasing hormone (prepro-GHRH; 12.3 kDa) precursor, like other neuropeptide precursors, undergoes proteolytic cleavage to give rise to mature GHRH, which is the primary stimulatory regulator of pituitary GH secretion. In this study we present the first model of in vitro pro-GHRH processing. Using pulse-chase analysis, we demonstrate that at least five peptide forms in addition to GHRH are produced. The pro-GHRH (after removal of its signal peptide, 10.5 kDa) is first processed to an 8.8-kDa intermediate form that is cleaved to yield two products: the 5.2-kDa GHRH and GHRH-related peptide (GHRH-RP; 3.6 kDa). GHRH-RP is a recently described peptide derived from proteolytic processing of pro-GHRH that activates stem cell factor, a factor known to be essential for hemopoiesis, spermatogenesis, and melanocyte function. Further cleavage results in a 3.5-kDa GHRH and a 2.2-kDa product of GHRH-RP.

Like GHRH, there is GHRH-RP immunostaining in hypothalamic neurons in the median eminence as detected by immunohistochemistry and immunoelectron microscopy. Based on deduced amino acid sequences of the pro-GHRH processing products, several peptides were synthesized and tested for their ability to stimulate the cAMP second messenger system. GHRH, GHRH-RP, and one of these peptides [prepro-GHRH-(75–92)-NH₂] all significantly stimulated the PKA pathway. This work delineates a new model of pro-GHRH processing and demonstrates that novel peptides derived from this processing may have biological action.

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