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).
We cloned the mouse TRH receptor type 2 (mTRH-R2) gene, which is 92% identical with rat TRH-R2 and 50% identical with mTRH-R1 at the amino acid level, and identified an intron within the coding sequence that is not present in the TRH-R1 gene structure. Similar to its rat homolog, mTRH-R2 binds TRH with an affinity indistinguishable from mTRH-R1, signals via the phosphoinositide pathway like mTRH-R1, but exhibits a higher basal signaling activity than mTRH-R1. We found that regulator of G protein signaling 4 (RGS4), which differentially inhibits signaling by other receptors that couple to Gq, inhibits TRH-stimulated signaling via mTRH-R1 and mTRH-R2 to similar extents. In contrast, other RGS proteins including RGS7, RGS9, and GAIP had no effect on signaling by mTRH-R1 or mTRH-R2 demonstrating the specificity of RGS4 action. Interestingly, RGS4 markedly inhibited basal signaling by mTRH-R2. Inhibition of basal signaling of mTRH-R2 by RGS4 suggests that modulation of agonist-independent signaling may be an important mechanism of regulation of G protein-coupled receptor activity under normal physiologic circumstances.
Harder
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S
Institut für Zellbiochemie und klinische Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany.
Lu
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Wang
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W
Buck
F
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Gershengorn
M C
MC
Bruhn
T O
TO
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D003001:Cloning, Molecular; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D020710:RGS Proteins / Q000494:pharmacology*; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
D020033:Protein Isoforms; D020710:RGS Proteins; D018025:Receptors, Thyrotropin-Releasing Hormone; C098799:RGS4 protein; D013973:Thyrotropin-Releasing Hormone