General

Thyrotropin-releasing hormone (TRH) is a tripeptide, pyroGlu-His-Proamide, that is synthesized in the hypothalamus and released into the hypothalamic-pituitary portal circulation to act on the pituitary [2-3] TRH is produced in many other tissues, especially within the nervous system, where it appears to act as a neurotransmitter/neuromodulator. TRH appears to initiate all of these effects by interacting with receptors that belong to the Class A G protein-coupled receptor (GPCR) family. In 1990, the first TRH receptor (TRH-R), later named type 1 TRH receptor, TRH₁, was cloned from a mouse pituitary tumor cDNA library [16] and then orthologous receptors were cloned from a number of different species including rat [5,20], chicken, cow, catostomus commersoni and humans [7,14]. The human TRH receptor, TRHR), is 90.3% and 89.2% homologous to the mouse and rat type 1 receptors at the DNA level, respectively; the three receptors exhibit approximately 95% homology at the amino acid level. In 1998, a second subtype of the TRH receptor (TRH₂) was identified in rat [4,13,15], mouse [11] and several other species; TRH₂ has not been found in humans. Amino acid sequence alignments of the two types of TRH receptors from the same species reveal a 50% overall identity. Of note, most of the structural research on TRH receptors has been performed with TRH₁.

TRH₁ signalling

TRH₁ signal transduction is mediated primarily by coupling to G_q/11 proteins [1,12]. TRH₁ activation leads to stimulation of phosphoinositide-specific phospholipase C, which stimulates phosphatidylinositol 4,5-P₂(PIP₂) hydrolysis to form inositol 1,4,5-triphosphosphate (IP₃) and 1,2-diacylglycerol (DAG). These second messengers stimulate increases in intracellular calcium and activation of protein kinase C. TRH₁ also stimulates calcium/calmodulin-dependent protein kinase and mitogen-activated protein kinase. TRH₁ also appears to couple to G_i2, G_i3, and to a G_s-like protein that does not activate adenylyl cyclase. Although TRH₁ and TRH₂ signal via the same pathways, these receptors show marked differences in basal signalling activities in that TRH₂ exhibits marked TRH-independent signalling activity [19].

TRH₁ structure

A model of mouse TRH₁ has been constructed based on homology to the x-ray crystallographic structure of bovine rhodopsin that appears to be a good model for TRH₁ because a number of its predictions have been shown by experimentation to be correct [10]. The model of the binding pocket of TRH₁ showed that the positions of Tyr¹⁰⁶ in transmembrane helix -3 (TMH-3), Tyr²⁸² in TMH-6, and Arg³⁰⁶ in TMH-7 are important for TRH binding. This model placed the binding pocket for TRH in the upper half of the transmembrane domain. This binding pocket location is similar to those found for small nonpeptide ligands.

Pharmacology

TRH is the only known naturally-occurring, high affinity ligand for TRH receptors. Of the many TRH analogues synthesized, only (N^τ-methyl)His-TRH (MeTRH) has been shown to exhibit a higher affinity at TRH receptors than TRH [18]. Recently, it was shown that several TRH analogues with affinities lower than TRH exhibited higher efficacies than TRH at TRH₁ [8,17]. There are several small organic compounds that act as antagonists at TRH receptors but with relatively low affinity [6,9,19].

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11. Harder S, Lu X, Wang W, Buck F, Gershengorn MC, Bruhn TO. (2001) Regulator of G protein signaling 4 suppresses basal and thyrotropin releasing-hormone (TRH)-stimulated signaling by two mouse TRH receptors, TRH-R(1) and TRH-R(2). Endocrinology, 142 (3): 1188-94. [PMID:11181534]

12. Hsieh KP, Martin TF. (1992) Thyrotropin-releasing hormone and gonadotropin-releasing hormone receptors activate phospholipase C by coupling to the guanosine triphosphate-binding proteins Gq and G11. Mol Endocrinol, 6 (10): 1673-81. [PMID:1333052]

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15. O'Dowd BF, Lee DK, Huang W, Nguyen T, Cheng R, Liu Y, Wang B, Gershengorn MC, George SR. (2000) TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1. Mol Endocrinol, 14 (1): 183-93. [PMID:10628757]

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19. Wang W, Gershengorn MC. (1999) Rat TRH receptor type 2 exhibits higher basal signaling activity than TRH receptor type 1. Endocrinology, 140 (10): 4916-9. [PMID:10499553]

20. Zhao D, Yang J, Jones KE, Gerald C, Suzuki Y, Hogan PG, Chin WW, Tashjian Jr AH. (1992) Molecular cloning of a complementary deoxyribonucleic acid encoding the thyrotropin-releasing hormone receptor and regulation of its messenger ribonucleic acid in rat GH cells. Endocrinology, 130 (6): 3529-36. [PMID:1317787]