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This version published online on February 23, 2006
Endocrinology, doi:10.1210/en.2005-1609
A more recent version of this article appeared on June 1, 2006
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Submitted on December 19, 2005
Accepted on February 15, 2006

Thyroid Hormones Selectively Regulate the Post-translational Processing of ProThyrotropin Releasing Hormone (ProTRH) in the Paraventricular Nucleus of the Hypothalamus

Mario Perello, Theodore Friedman, Veronica Paez-Espinoza, Xiaoxiong Shen, Ronald C. Stuart, and Eduardo A. Nillni*

Division of Endocrinology, Department of Medicine Brown University/Rhode Island Hospital, Providence, RI 02903, Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine & Sciences-UCLA School of Medicine, Los Angeles, CA 90059, and Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02903

* To whom correspondence should be addressed. E-mail: Eduardo_Nillni{at}Brown.edu.

Over the last few years our laboratory has demonstrated that different physiological conditions or stressors affect the post-translational processing of hypophysiotropic and non-hypophysiotropic proThyrotropin Releasing Hormone (proTRH), and consequently the output of TRH and other proTRH-derived peptides. These alterations in proTRH processing are generally associated with parallel changes in the levels of two members of the family of prohormone convertases 1/3 and 2 (PC1/3, PC2). An important regulator of proTRH is thyroid hormone, which is the peripheral end product of the hypothalamic (TRH)-pituitary (TSH)-thyroid (T3/4) (HPT) axis. In this study, we investigated the effect of the thyroid status on the processing of proTRH inside and outside of the HPT axis. Our data showed that high levels of thyroid hormone down-regulated PC1/3 and PC2 and TRH synthesis which led to an accumulation of intermediate forms of proTRH processing. Conversely, low levels of thyroid hormone up-regulated proTRH synthesis and PC1/3 and PC2 levels. Control of the activity of PCs and proTRH processing occurred specifically in the PVN, while no changes due to thyroid status were found in the lateral hypothalamus or preoptic area. The post-translational regulation of proTRH processing in the PVN by thyroid status is a novel aspect of the regulation of the HPT axis, which may have important implications in the pathophysiology of hypo and hyperthyroidism.
Key words: proTRH Processing • Hypothalamus • Prohormone convertases • Thyroid Hormones • Hypothyroidism • Hyperthyroidism




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