TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1

TRH (thyroliberin) is a tripeptide (pGlu-His-ProNH(2)) that signals via G p rotein-coupled receptors. Until recently, only a single receptor for TRH wa s known (TRH-R1), but two groups identified a second receptor, TRH-RP. We i ndependently discovered TRH-RP. Using an extensive set of TRH analogs, we f ound no differences in TRH-R1 and TRH-R2 binding or in acute stimulation of signaling. TRH-RP was more rapidly internalized upon binding TRH and exhib ited a greater level of TRH-induced down-regulation than TRH-R1. During pro longed exposure to TRH, cells expressing TRH-RP exhibited a lower level of gene induction than cells expressing TRH-R1. TRH-R2 receptor mRNA was prese nt in very discrete nuclei and regions of rat brain. A major mRNA transcrip t for TRH-RS was seen in the cerebral cortex, pens, thalamus, hypothalamus, and midbrain with faint bands found in the striatum and pituitary. The ext ensive distribution of TRH-RP in the brain suggests that it mediates many o f the known functions of TRH that are not transduced by TRH-RI. The variati ons in agonist-induced internalization and down-regulation/desensitization, and anatomic distribution of TRH-RP compared with TRH-R1, suggest importan t functional differences between the two receptors.