Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism

1 Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles School of Medicine, Los Angeles; 2 Division of Urology, Research and Education Institute, Harbor-University of California Los Angeles Medical Center, Torrance; 3 College of Pharmacy, Western University of Health Sciences, Pomona, California; and 4 Division of Endocrinology, Department of Medicine, Brown Medical School, Rhode Island Hospital, Providence, Rhode Island Submitted 16 June 2006 ; accepted in final form 21 August 2006 The prohormone convertases (PCs), PC1/3 and PC2, are involved in the tissue-specific endoproteolytic posttranslational processing of many hormonal precursors within the secretory pathway. One important prohormone, pro-thyrotropin-releasing hormone (TRH), is expressed in both hypophysiotropic (where it regulates the secretion of thyroid-stimulating hormone) and nonhypophysiotropic regions of the brain. Pro-TRH is processed at specific sites in the secretory pathway, primarily by PC1/3 followed by PC2. We hypothesized that thyroid hormone status in specific nuclei of the brain would alter pro-TRH processing by inducing changes in PC1/3 and PC2 expression. Therefore, we examined pro-TRH, PC1/3, and PC2 coexpression and coregulation in the paraventricular nucleus (PVN), lateral hypothalamus (LH), and ventromedial nucleus (VMN) of hypothyroid and euthyroid rats. Our results show that 6- n- propyl-2-thiouracil (PTU) treatment producing hypothyroidism induced a significant increase in the expression of PC1/3, PC2, and pro-TRH in the PVN and LH, but not VMN. When confocal studies were performed, an increase in colocalization of PC1/3 or PC2 in pro-TRH was observed only in PVN, a response that was especially prominent in the ventral and medial areas of the PVN. PTU did not regulate colocalization in the VMH or LH. Regulation of colocalization of processing enzyme and prohormone expression is a novel mechanism to alter hormonal biosynthesis. posttranslational processing; hyperthyroidism; hypothyroidism; prohormone convertase; hypothalamus; pro-thyrotropin-releasing hormone; peptide Address for reprint requests and other correspondence: T. C. Friedman, Charles R. Drew Univ. of Medicine & Sciences, Division of Endocrinology, 1731 E. 120th St., Los Angeles, CA 90059 (e-mail: tefriedm{at}cdrewu.edu )