Submitted on June 16, 2006
Accepted on August 21, 2006
Cellular co-localization and co-regulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism
Veronica Paez Espinosa1, Monica Ferrini2, Xiaoxiong Shen3, Kabirullah Lutfy, Eduardo A. Nillni4, and Theodore C. Friedman5*
1 Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine & Sciences-UCLA School of Medicine, Los Angeles, California, United States
2 Division of Urology, Research and Education Institute, Harbor-UCLA Medical Center, Los Angeles, California, United States
3 Los Angeles, California, United States; Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine & Sciences-UCLA School of Medicine, Los Angeles, California, United States
4 Division of Endocrinology, Department of Medicine, Brown University, Providence, Rhode Island, United States; Brown University
5 Endocrinology, Charles R. Drew University, los angeles, California, United States
* To whom correspondence should be addressed. E-mail: tefriedm{at}cdrewu.edu.
The prohormone convertases (PCs), PC1/3 and PC2, are involved in the tissue-specific endoproteolytic post-translational processing of many hormonal precursors within the secretory pathway. One important prohormone, pro-TRH, is expressed in both hypophysiotropic (where it regulates the secretion of thyroid-stimulating hormone) and non-hypophysiotropic 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 co-expression and co-regulation 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 co-localization of PC1/3 or PC2 in pro-TRH was observed only in PVN sites, a response that was especially prominent in the ventral and medial areas of the PVN. PTU did not regulate co-localization in the VMH or LH. Regulation of co-localization of processing enzyme and prohormone expression is a novel mechanism to alter hormonal biosynthesis.
