# TRH

## Overview
The TRH gene encodes the thyrotropin-releasing hormone, a tripeptide hormone that plays a pivotal role in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. This hormone is synthesized in the hypothalamus and is crucial for stimulating the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH) and prolactin, thereby influencing thyroid function and overall metabolic regulation (Monga2008Chemistry; JosephBravo201560). The TRH protein is categorized as a neuropeptide and functions by binding to the TRH receptor, a G protein-coupled receptor, to initiate a signaling cascade that affects calcium homeostasis and activates protein kinase C (JosephBravo201560). Beyond its endocrine role, TRH also acts as a neuromodulator, impacting neurotransmitter release and various physiological processes such as metabolism, growth, and development (Yarbrough2007Thyrotropinreleasing; JosephBravo201560). The gene's expression and the hormone's activity are critical for maintaining energy homeostasis and integrating autonomic and endocrine signals.

## Structure
Thyrotropin-releasing hormone (TRH) is a tripeptide composed of L-pyroglutamyl-L-histidyl-L-prolineamide (L-pGlu-L-His-L-ProNH2) (Monga2008Chemistry). The primary structure of TRH consists of these three amino acids linked in sequence, with a pyroglutamic acid at the N-terminus and a proline amide at the C-terminus (Folkers1971Structure; Nair1970Structure). The N-terminal pyroglutamic acid is crucial for the molecule's stability and receptor binding, forming specific hydrogen bonds with receptor sites (Monga2008Chemistry).

TRH does not have a complex secondary, tertiary, or quaternary structure due to its small size. However, its conformation is important for biological activity, with studies suggesting a 'hair pin turn' conformation as more stable than an extended form (Monga2008Chemistry). The histidine residue plays a significant role in receptor interaction, particularly with the TRH receptor (TRH-R), which is a G protein-coupled receptor (Monga2008Chemistry).

Post-translational modifications of TRH include amidation at the C-terminus, which is essential for its activity (Monga2008Chemistry). The biosynthesis of TRH involves several steps, including cleavage and cyclization, to produce the active hormone from its precursor (Monga2008Chemistry). There are no known splice variant isoforms of TRH.

## Function
Thyrotropin-releasing hormone (TRH) is a tripeptide hormone synthesized in the hypothalamus, primarily in the paraventricular nucleus. It plays a critical role in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis by stimulating the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH) and prolactin (Monga2008Chemistry; JosephBravo201560). TRH binds to its receptor, TRHR1, on thyrotrophs in the anterior pituitary, initiating a signaling cascade that involves the Gq/11 protein and phospholipase C, which affects calcium homeostasis and activates protein kinase C (JosephBravo201560). This process leads to the synthesis and release of TSH, which in turn stimulates the thyroid gland to produce thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3) (Fröhlich2019The).

TRH is also involved in broader neuromodulatory roles beyond the HPT axis, influencing neurotransmitter release and various physiological processes such as metabolism, growth, and development (Yarbrough2007Thyrotropinreleasing; JosephBravo201560). It affects energy homeostasis, food intake, and integrates autonomic and endocrine signals, contributing to the regulation of behavioral and energy homeostasis (Yarbrough2007Thyrotropinreleasing).

## Clinical Significance
Mutations or disruptions in the thyrotropin-releasing hormone (TRH) gene can lead to significant clinical conditions, primarily affecting the hypothalamic-pituitary-thyroid (HPT) axis. One notable condition is tertiary hypothyroidism, characterized by elevated thyroid-stimulating hormone (TSH) levels and decreased thyroid hormone levels. This condition arises due to insufficient TRH production, which leads to reduced stimulation of the pituitary gland and subsequently low thyroid hormone levels (Yamada1997Tertiary). 

TRH deficiency can also result in altered TSH bioactivity due to changes in glycosylation patterns, leading to higher serum TSH levels but lower serum T4 levels (Nikrodhanond2006Dominant). This deficiency is associated with impaired insulin secretion, resulting in hyperglycemia, which suggests a potential link between TRH gene abnormalities and diabetes mellitus (Yamada1997Tertiary).

Additionally, mutations in the TRH receptor gene can lead to central hypothyroidism, where there is resistance to TRH, resulting in increased TSH production. This condition is associated with symptoms of hypothyroidism but does not typically cause severe cognitive or neurological deficits (Fröhlich2019The). These findings underscore the critical role of TRH in maintaining normal endocrine and metabolic functions.


## References


[1. (Yarbrough2007Thyrotropinreleasing) G.G. Yarbrough, J. Kamath, A. Winokur, and A.J. Prange. Thyrotropin-releasing hormone (trh) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Medical Hypotheses, 69(6):1249–1256, January 2007. URL: http://dx.doi.org/10.1016/j.mehy.2007.04.005, doi:10.1016/j.mehy.2007.04.005. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.mehy.2007.04.005)

[2. (JosephBravo201560) Patricia Joseph-Bravo, Lorraine Jaimes-Hoy, Rosa-María Uribe, and Jean-Louis Charli. 60 years of neuroendocrinology: trh, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis. Journal of Endocrinology, 226(2):T85–T100, June 2015. URL: http://dx.doi.org/10.1530/joe-15-0124, doi:10.1530/joe-15-0124. This article has 82 citations and is from a peer-reviewed journal.](https://doi.org/10.1530/joe-15-0124)

[3. (Fröhlich2019The) Eleonore Fröhlich and Richard Wahl. The forgotten effects of thyrotropin-releasing hormone: metabolic functions and medical applications. Frontiers in Neuroendocrinology, 52:29–43, January 2019. URL: http://dx.doi.org/10.1016/j.yfrne.2018.06.006, doi:10.1016/j.yfrne.2018.06.006. This article has 46 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.yfrne.2018.06.006)

[4. (Nikrodhanond2006Dominant) Amisra A. Nikrodhanond, Tania M. Ortiga-Carvalho, Nobuyuki Shibusawa, Koshi Hashimoto, Xiao Hui Liao, Samuel Refetoff, Masanobu Yamada, Masatomo Mori, and Fredric E. Wondisford. Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis. Journal of Biological Chemistry, 281(8):5000–5007, February 2006. URL: http://dx.doi.org/10.1074/jbc.m511530200, doi:10.1074/jbc.m511530200. This article has 73 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m511530200)

[5. (Folkers1971Structure) K. Folkers, F. Enzmann, J. Boeler, C. Y. Bowers, and A. V. Schally. Structure and synthesis of the thyrotropin-releasing hormone. Journal of Medicinal Chemistry, 14(6):469–474, June 1971. URL: http://dx.doi.org/10.1021/jm00288a001, doi:10.1021/jm00288a001. This article has 26 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1021/jm00288a001)

[6. (Nair1970Structure) R. M. G. Nair, J. F. Barrett, C. Y. Bowers, and A. V. Schally. Structure of porcine thyrotropin-releasing hormone. Biochemistry, 9(5):1103–1106, March 1970. URL: http://dx.doi.org/10.1021/bi00807a008, doi:10.1021/bi00807a008. This article has 159 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi00807a008)

[7. (Yamada1997Tertiary) Masanobu Yamada, Yumiko Saga, Nobuyuki Shibusawa, Jyunko Hirato, Masami Murakami, Toshiharu Iwasaki, Koshi Hashimoto, Teturou Satoh, Katsumi Wakabayashi, Makoto M. Taketo, and Masatomo Mori. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. Proceedings of the National Academy of Sciences, 94(20):10862–10867, September 1997. URL: http://dx.doi.org/10.1073/pnas.94.20.10862, doi:10.1073/pnas.94.20.10862. This article has 161 citations.](https://doi.org/10.1073/pnas.94.20.10862)

[8. (Monga2008Chemistry) Vikramdeep Monga, Chhuttan Meena, Navneet Kaur, and Rahul Jain. Chemistry and biology of thyrotropin-releasing hormone (trh) and its analogs. Current Medicinal Chemistry, 15(26):2718–2733, November 2008. URL: http://dx.doi.org/10.2174/092986708786242912, doi:10.2174/092986708786242912. This article has 48 citations and is from a peer-reviewed journal.](https://doi.org/10.2174/092986708786242912)