Thyrotropin-releasing hormone receptor 2 (TRHR2) (TRHR2)

Thyrotropin-releasing hormone receptor 2 (TRHR2) is a G protein-coupled receptor (GPCR) that serves as a high-affinity binding site for the hypothalamic tripeptide thyrotropin-releasing hormone (TRH) (UniProt: P56485). While the closely related TRHR1 is primarily responsible for the endocrine functions of TRH in the pituitary gland, TRHR2 is predominantly localized within the central nervous system, including the thalamus, brainstem, and spinal cord (IUPHAR/BPS Guide to Pharmacology). It plays a critical role in modulating non-endocrine functions such as arousal, locomotor activity, and nociception (Sun et al., 2003). A significant pharmacological challenge is that while TRHR2 is functional in rodents, the human ortholog is widely considered a pseudogene, which limits the direct translation of TRHR2-specific therapies to human patients (O'Dowd et al., 2000). Nevertheless, TRH analogs like taltirelin have been developed to target TRH receptors for the treatment of neurodegenerative diseases and spinal cord injuries. Therapeutic development focuses on achieving subtype selectivity to avoid the systemic endocrine side effects associated with TRHR1 activation, such as excessive thyroid-stimulating hormone (TSH) release. Research continues to explore the potential of TRHR2 as a target for analeptic and neuroprotective agents in animal models. The receptor signals primarily through the Gq/11-phospholipase C pathway, leading to increased intracellular calcium levels.

Other names

TRH-R2TRH receptor 2Thyrotropin-releasing hormone receptor type 2

Agonist of G protein-coupled receptor signaling, specifically activating the phospholipase C (PLC) pathway via Gq/11 proteins.