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% identi cal with rat TRH-RB 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 w ith an affinity indistinguishable from mTRH-R1, signals via the phosphoinos itide pathway like mTRH-R1, but exhibits a higher basal signaling activity than mTRH-R1. We found that regulator of G protein signaling 4 (RGS4), whic h differentially inhibits signaling by other receptors that couple to Gq, i nhibits TRH-stimulated signaling via mTRH-R1 and mTRH-R2 to similar extents . In contrast, other RGS proteins including RGS7, RGS9, and GAIP had no eff ect on signaling by mTRH-R1 or mTRH-R2 demonstrating the specificity of RGS 4 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 regulati on of G protein-coupled receptor activity under normal physiologic circumst ances.