Desensitization, trafficking, and resensitization of the pituitary thyrotropin-releasing hormone receptor
- 1Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA
- 2Department of Science and Mathematics, National Technical Institute for the Deaf, Rochester Institute of Technology, Rochester, NY, USA
- 3Department of Pharmacology, University of Washington, Seattle, WA, USA
The pituitary receptor for thyrotropin-releasing hormone (TRH) is a calcium-mobilizing G protein-coupled receptor (GPCR) that signals through Gq/11, elevating calcium, and activating protein kinase C. TRH receptor signaling is quickly desensitized as a consequence of receptor phosphorylation, arrestin binding, and internalization. Following activation, TRH receptors are phosphorylated at multiple Ser/Thr residues in the cytoplasmic tail. Phosphorylation catalyzed by GPCR kinase 2 (GRK2) takes place rapidly, reaching a maximum within seconds. Arrestins bind to two phosphorylated regions, but only arrestin bound to the proximal region causes desensitization and internalization. Phosphorylation at Thr365 is critical for these responses. TRH receptors internalize in clathrin-coated vesicles with bound arrestin. Following endocytosis, vesicles containing phosphorylated TRH receptors soon merge with rab5-positive vesicles. Over approximately 20 min these form larger endosomes rich in rab4 and rab5, early sorting endosomes. After TRH is removed from the medium, dephosphorylated receptors start to accumulate in rab4-positive, rab5-negative recycling endosomes. The mechanisms responsible for sorting dephosphorylated receptors to recycling endosomes are unknown. TRH receptors from internal pools help repopulate the plasma membrane. Dephosphorylation of TRH receptors begins when TRH is removed from the medium regardless of receptor localization, although dephosphorylation is fastest when the receptor is on the plasma membrane. Protein phosphatase 1 is involved in dephosphorylation but the details of how the enzyme is targeted to the receptor remain obscure. It is likely that future studies will identify biased ligands for the TRH receptor, novel arrestin-dependent signaling pathways, mechanisms responsible for targeting kinases and phosphatases to the receptor, and principles governing receptor trafficking.
Keywords: dephosphorylation, desensitization, internalization, phosphorylation, Rab, thyrotropin-releasing hormone, trafficking, TRH receptor
Citation: Hinkle PM, Gehret AU and Jones BW (2012) Desensitization, trafficking, and resensitization of the pituitary thyrotropin-releasing hormone receptor. Front. Neurosci. 6:180. doi: 10.3389/fnins.2012.00180
Received: 02 October 2012; Paper pending published: 02 November 2012;
Accepted: 26 November 2012; Published online: 13 December 2012.
Edited by:Liliane Schoofs, Catholic University of Leuven, Belgium
Reviewed by:Perry Barrett, University of Aberdeen, UK
Leo T. Lee, The University of Hong Kong, Hong Kong
Copyright: © 2012 Hinkle, Gehret and Jones. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Patricia M. Hinkle, Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue Rochester, Rochester, NY 14642, USA. e-mail: email@example.com