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Correlation between Basal Signaling and Internalization of Thyrotropin-Releasing Hormone Receptors: Evidence for Involvement of Similar Receptor Conformations

The Division of Molecular Medicine, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021; and the Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-8029

Address all correspondence and requests for reprints to: Marvin C. Gershengorn, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 50 South Drive, MSC 8029, Bethesda, Maryland 20892-8029. E-mail: . marving{at}intra.niddk.nih.gov

Previous studies have shown that rat thyrotropin-releasing hormone (TRH) receptor type 2 exhibits higher basal signaling activity and internalizes more rapidly upon agonist binding than rat TRH receptor type 1. The mouse TRH receptor type 2 (mR2) was recently cloned and, similar to its rat homolog, shows a higher basal signaling activity than mR1. Taking advantage of the high degree of sequence homology between mR1 and mR2, we used chimeras/mutants of these receptors to gain insight into the properties of the receptors that influence internalization and basal signaling. Chimeric receptors that have the mR1 extracellular and transmembrane domains with the carboxyl terminus and intracellular loops of mR2 (R1/R2-tail; R1/R2-I3,tail; R1/R2-I2,3,tail; R1/R2-I1,2,3,tail) exhibited internalization rates and basal activities that were similar to that of mR1. In contrast, a chimeric receptor with the extracellular and transmembrane domains of mR2 and the carboxyl terminus of mR1 exhibited the more rapid internalization rate and higher basal signaling activity characteristic of mR2. We showed previously that mutation of a highly conserved tryptophan to alanine caused mR1 to exhibit a high basal signaling activity and rapid internalization rate. In contrast, mutation of this tryptophan to alanine in mR2 decreased the rate of internalization and inhibited basal signaling activity. The rates of receptor internalization did not correlate with the binding affinities, coupling efficiencies, or potencies of the receptors. Thus, we observed that receptors with more rapid internalization rates showed relatively higher basal signaling activities, whereas receptors with lower basal signaling activities showed slower internalization rates. These data suggest that similar receptor conformations are required for productive coupling to signaling G proteins and to proteins involved in internalization.

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