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-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.
O'Dowd
B F
BF
Department of Pharmacology, University of Toronto, Ontario, Canada.
Lee
D K
DK
Huang
W
W
Nguyen
T
T
Cheng
R
R
Liu
Y
Y
Wang
B
B
Gershengorn
M C
MC
George
S R
SR
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019556:COS Cells; D003001:Cloning, Molecular; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; D008565:Membrane Proteins; C114581:Mlnr protein, rat; D043562:Receptors, G-Protein-Coupled; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone