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PreproTRH_178–199 and Two Novel Peptides (pFQ7 and pSE14) Derived from Its Processing, Which Are Produced in the Paraventricular Nucleus of the Rat Hypothalamus, Are Regulated during Suckling¹

Division of Endocrinology (E.A.N., R.B.T.), Department of Medicine, Brown University School of Medicine, Rhode Island Hospital, Providence, Rhode Island 02903; Maryland Psychiatric Research Center (J.I.K.), University of Maryland School of Medicine, Baltimore, Maryland 21228; Department of Psychiatry and Behavioral Sciences (F.A.), Northwestern University Medical School, Chicago, Illinois 60611; and Laboratory of Biochemical Neuroendocrinology (N.G.S.), Clinical Research Institute of Montréal, Montréal, Québec H2W1R7, Canada

Address all correspondence and requests for reprints to: Dr. Eduardo A. Nillni, Division of Endocrinology, Rhode Island Hospital, 55 Claverick Street, Room 400/430, Providence, Rhode Island 02903. E-mail: Eduardo_Nillni{at}Brown.edu

Suckling increases preproTRH messenger RNA in hypothalamic paraventricular neurons (PVN) and also markedly increases TRH release during the first period of lactation. Whether lactation alters preproTRH processing resulting in the generation of novel proTRH-derived peptides that may be involved in the regulation of PRL secretion lactation is not known. Therefore, in the present study we determine whether some other peptides derived from proTRH potentially contribute to lactation-induced PRL secretion. We have recently demonstrated that two members of the family of prohormone convertases PC1 and PC2 play a significant role in proTRH processing. PC1 is the major contributor in proTRH processing, whereas PC2 may have a specific role in cleaving TRH from its extended forms. In this study, we used a recombinant vaccinia virus system to coexpress rat preproTRH complementary DNA with PC1, PC2, and the neuropeptide 7B2 in GH4C1 cells (somatomammothophs, rat). We found that two novel peptides, preproTRH_178–184 (pFQ₇), and preproTRH_186–199 (pSE₁₄), were formed after the cleavage of their precursor preproTRH_178–199 (pFE₂₂) by only PC2. Their formation was confirmed by microsequence analysis. Anatomical analyses revealed that these peptides are also found in the rat PVN. In addition, we found that pFE₂₂, pSE₁₄ and pFQ₇ produced a dose-dependent release of PRL from primary cultures of pituitary cells compared with one of the well studied secretagogues of PRL, TRH. To establish whether these peptides might play a role in vivo in the regulation of PRL release, we took rat litters on postnatal day 4, separated the pups from their mothers for 6 h, and then reunited the pups and mothers for 45 min. At the end of this period, the mothers were killed, acidic extracts of microdissected PVN were prepared and subjected to SDS-PAGE, followed by slicing and analysis by pFE₂₂ RIA. Forty-five minutes of suckling induced a marked 6-fold increase in serum levels of PRL. In addition, PVN levels of pFE₂₂ and pSE₁₄ increased approximately 5-fold during the same period in the acutely suckling females. Lactating animals that were separated from their litters and never reunited with their pups had low levels of PRL, and pFE₂₂ and pSE₁₄. These data provide the first evidence for alterations in proTRH processing in the PVN during lactation and suggest that the products of this altered processing may play a physiological role in the regulation of PRL secretion.

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