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Regulator of G Protein Signaling 4 Suppresses Basal and Thyrotropin Releasing-Hormone (TRH)-Stimulated Signaling by Two Mouse TRH Receptors, TRH-R₁ and TRH-R₂¹

Institut für Zellbiochemie und klinische Neurobiologie (S.H., F.B., T.O.B.), Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany; and Division of Molecular Medicine (X.L., W.W., M.C.G.), Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021-4896

Address all correspondence and requests for reprints to: Dr. Marvin C. Gershengorn, Weill Medical College of Cornell University, 1300 York Avenue, Room A328, New York, New York 10021-4896. E-mail: mcgersh{at}med.cornell.edu

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.

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