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Regulated Dimerization of the Thyrotropin-Releasing Hormone Receptor Affects Receptor Trafficking But Not Signaling

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642

Address all correspondence and requests for reprints to: Patricia M. Hinkle, Department of Pharmacology and Physiology, University of Rochester Medical Center, Box 711, Rochester, New York 14642. E-mail: Patricia_Hinkle{at}urmc.rochester.edu.

To investigate the function of dimerization of the TRH receptor, a controlled dimerization system was developed. A variant FK506 binding protein (FKBP) domain was fused to the receptor C terminus and dimerization induced by incubating cells with dimeric FKBP ligand, AP20187. The TRH receptor-fusion bound hormone and signaled normally. Addition of dimerizer to cells expressing the receptor-FKBP fusion dramatically increased the fraction of receptor running as dimer on SDS-PAGE. AP20187 caused dimerization in a time- and concentration-dependent manner, acting within 1 min. Dimerizer had no effect on TRH receptors lacking the FKBP domain, and its effects were blocked by excess monomeric FKBP ligand. AP20187-induced dimerization did not cause receptor phosphorylation, inositol phosphate production, or ERK1/2 activation, and dimerizer did not alter signaling by TRH. Induced dimerization did, however, alter TRH receptor trafficking. TRH promoted greater receptor internalization in cells treated with AP20187 but not monomeric ligand, based on loss of surface binding sites and immunostaining. Dimerization increased the rate of internalization of TRH receptors and decreased the apparent rate of receptor recycling. AP20187 enhanced the small amount of TRH-induced receptor internalization when the receptor-FKBP fusion protein was expressed in cells lacking ß-arrestins. The results show that controlled dimerization of the TRH receptor potentiates hormone-induced receptor trafficking.

This article has been cited by other articles:

				G. J. Song, B. W. Jones, and P. M. Hinkle Dimerization of the thyrotropin-releasing hormone receptor potentiates hormone-dependent receptor phosphorylation PNAS, November 13, 2007; 104(46): 18303 - 18308. [Abstract] [Full Text] [PDF]