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TRH-R2 Exhibits Similar Binding and Acute Signaling but Distinct Regulation and Anatomic Distribution Compared with TRH-R1

Departments of Pharmacology (B.F.O., D.K.L., Y.L., S.R.G.) and Medicine (S.R.G.) University of Toronto Toronto, Ontario M5S 1A8, Canada Centre for Addiction and Mental Health (B.F.O., T.N., R.C., S.R.G.) Toronto, Ontario, M5S 2S1, Canada Division of Molecular Medicine (W.H., B.W., M.C.G.) Department of Medicine Weill Medical College of Cornell University New York, New York 10021

TRH (thyroliberin) is a tripeptide (pGlu-His-ProNH₂) that signals via G protein-coupled receptors. Until recently, only a single receptor for TRH was known (TRH-R1), but two groups identified a second receptor, TRH-R2. We independently discovered TRH-R2. Using an extensive set of TRH analogs, we found no differences in TRH-R1 and TRH-R2 binding or in acute stimulation of signaling. TRH-R2 was more rapidly internalized upon binding TRH and exhibited a greater level of TRH-induced down-regulation than TRH-R1. During prolonged exposure to TRH, cells expressing TRH-R2 exhibited a lower level of gene induction than cells expressing TRH-R1. TRH-R2 receptor mRNA was present in very discrete nuclei and regions of rat brain. A major mRNA transcript for TRH-R2 was seen in the cerebral cortex, pons, thalamus, hypothalamus, and midbrain with faint bands found in the striatum and pituitary. The extensive distribution of TRH-R2 in the brain suggests that it mediates many of the known functions of TRH that are not transduced by TRH-R1. The variations in agonist-induced internalization and down-regulation/desensitization, and anatomic distribution of TRH-R2 compared with TRH-R1, suggest important functional differences between the two receptors.

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