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J. Biol. Chem., Vol. 277, Issue 52, 50422-50430, December 27, 2002

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Homo- and Hetero-oligomerization of Thyrotropin-releasing Hormone (TRH) Receptor Subtypes
DIFFERENTIAL REGULATION OF -ARRESTINS 1 AND 2^*

Aylin C. Hanyaloglu^§, Ruth M. Seeber, Trudy A. Kohout^¶, Robert J. Lefkowitz^¶, and Karin A. Eidne^§

From the  7TM Receptor Laboratory, Western Australian Institute for Medical Research (WAIMR), University of Western Australia, Centre for Medical Research, and the ^§ Keogh Institute for Medical Research, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA 6009, Australia and the ^¶ Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 21170

G-protein-coupled receptors (GPCRs) are regulated by a complex network of mechanisms such as oligomerization and internalization. Using the GPCR subtypes for thyrotropin-releasing hormone (TRHR1 and TRHR2), the aim of this study was to determine if subtype-specific differences exist in the trafficking process. If so, we wished to determine the impact of homo- and hetero-oligomerization on TRHR subtype trafficking as a potential mechanism for the differential cellular responses induced by TRH. Expression of either -arrestin 1 or 2 promoted TRHR1 internalization. In contrast, only -arrestin 2 could enhance TRHR2 internalization. The preference for -arrestin 2 by TRHR2 was supported by the impairment of TRHR2 trafficking in mouse embryonic fibroblasts (MEFs) from either a -arrestin 2 knockout or a -arrestin 1/2 knockout, while TRHR1 trafficking was only abolished in MEFs lacking both -arrestins. The differential -arrestin-dependence of TRHR2 was directly measured in live cells using bioluminescence resonance energy transfer (BRET). Both BRET and confocal microscopy were also used to demonstrate that TRHR subtypes form hetero-oligomers. In addition, these hetero-oligomers have altered internalization kinetics compared with the homo-oligomer. The formation of TRHR1/2 heteromeric complexes increased the interaction between TRHR2 and -arrestin 1. This may be due to conformational differences between TRHR1/2 hetero-oligomers versus TRHR2 homo-oligomers as a mutant TRHR1 (TRHR1 C335Stop) that does not interact with -arrestins, could also enhance TRHR2/-arrestin 1 interaction. This study demonstrates that TRHR subtypes are differentially regulated by the -arrestins and also provides the first evidence that the interactions of TRHRs with -arrestin may be altered by hetero-oligomer formation.

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