Thyrotropin-releasing hormone (TRH) is a widely distributed tripeptide which acts as a hormone, a paracrine regulatory factor and a neurotransmitter/neuromodulator. It is expressed in many parts of the brain as well as in various peripheral tissues^1,2.

In the hypothalamus, TRH is secreted from the paraventricular nucleus (VPN) by TRH neurons prior to a post-translational processing from its precursor, pro-TRH. A key player in the regulation of the hypothalamus-pituitary-thyroid (HPT) axis, TRH is released into the hypophyseal portal circulation of the median eminence and reaches the pituitary, where it binds to TRH receptors, thereby stimulating the secretion of tyrothropin (thyroid-stimulating hormone; TSH). TSH, in turn, affects the thyroid to produce T₄ which is subsequently converted into its biologically-active analog, T₃ - a negative mediator of TRH. In the tanycytes, ependymal cells of glial origin located in close proximity to the VPN, T₄ is converted to T₃ by the enzyme deiodinase II (dio2) - a counterpart to deiodinase III (dio3) which conversely inactivates the above mentioned thyroid hormones, thus indirectly promoting the production of TRHs^3,4.

TRH receptor 1 (TRH-R1), the only identified TRH receptor in humans, is a G-protein coupled receptor (GPCR) abundant in the anterior pituitary, neuroendocrine system, autonomic nervous system and the visceral regions of the brain^2,5. Like all members of GPCRs, the TRH receptor has seven transmembrane domains, and extracellular N-terminus and intracellular C-terminal tail. TRH receptor couples Gq upon activation which in turn leads to the activation of phospholipase C⁵.

From a behavioral aspect, it was shown that TRH-coupled TRH-R1 increases cognitive arousal by directly exciting the sleep/wake system in the lateral hypothalamic area, and inhibits seizure activity in the hippocampus by facilitating GABA release. Conversely, its deficiency, as observed in mutant model mice, is linked to growth retardation, depression, and anxiety-like behavior^1,6,7.