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Thyroid Hormones Selectively Regulate the Posttranslational Processing of Prothyrotropin-Releasing Hormone in the Paraventricular Nucleus of the Hypothalamus

Division of Endocrinology, Department of Medicine Brown University/Rhode Island Hospital (M.P., R.C.S., E.A.N.), Providence, Rhode Island 02903; Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine and Sciences-University of California School of Medicine (T.F., V.P.-E., X.S.), Los Angeles, California 90059; and Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University (E.A.N.), Providence, Rhode Island 02903

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

Over the last few years, our laboratory has demonstrated that different physiological conditions or stressors affect the posttranslational processing of hypophysiotropic and nonhypophysiotropic 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 and PC2). An important regulator of proTRH is thyroid hormone, which is the peripheral end product of the hypothalamic (TRH)-pituitary (TSH)-thyroid (T_3/4) (HPT) axis. In this study we investigated the effect of thyroid status on the processing of proTRH inside and outside 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 paraventricular nucleus, whereas no change due to thyroid status was found in the lateral hypothalamus or preoptic area. The posttranslational regulation of proTRH processing in the paraventricular nucleus by thyroid status is a novel aspect of the regulation of the HPT axis, which may have important implications for the pathophysiology of hypo- and hyperthyroidism.

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