Format

Send to

Choose Destination
Cell Signal. 2016 May;28(5):531-540. doi: 10.1016/j.cellsig.2016.02.013. Epub 2016 Feb 17.

PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment.

Author information

1
J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, and the Department of Physiology and Pharmacology, University of Western Ontario, 100 Perth Dr. London, Ontario N6A 5K8, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Dr. Ottawa, Ontario K1H 8M5, Canada.
2
J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, and the Department of Physiology and Pharmacology, University of Western Ontario, 100 Perth Dr. London, Ontario N6A 5K8, Canada.
3
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 3K7, Canada.
4
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Dr. Ottawa, Ontario K1H 8M5, Canada. Electronic address: sferguso@uottawa.ca.

Abstract

Corticotropin-releasing factor (CRF) is a neuropeptide commonly associated with the hypothalamic-pituitary adrenal axis stress response. Upon release, CRF activates two G protein-coupled receptors (GPCRs): CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). Although both receptors contribute to mood regulation, CRFR1 antagonists have demonstrated anxiolytic and antidepressant-like properties that may be exploited in the generation of new pharmacological interventions for mental illnesses. Previous studies have demonstrated CRFR1 capable of heterologously sensitizing serotonin 2A receptor (5-HT2AR) signaling: another GPCR implicated in psychiatric disease. Interestingly, this phenomenon was dependent on Postsynaptic density 95 (PSD-95)/Disc Large/Zona Occludens (PDZ) interactions on the distal carboxyl termini of both receptors. In the current study, we demonstrate that endogenous PSD-95 can be co-immunoprecipitated with CRFR1 from cortical brain homogenate, and this interaction appears to be primarily via the PDZ-binding motif. Additionally, PSD-95 colocalizes with CRFR1 within the dendritic projections of cultured mouse neurons in a PDZ-binding motif-dependent manner. In HEK 293 cells, PSD-95 overexpression inhibited CRFR1 endocytosis, whereas PSD-95 shRNA knockdown enhanced CRFR1 endocytosis. Although PSD-95 does not appear to play a significant role in CRF-mediated cAMP or ERK1/2 signaling, PSD-95 was demonstrated to suppress β-arrestin2 recruitment: providing a potential mechanism for PSD-95's inhibition of endocytosis. In revisiting previously documented heterologous sensitization, PSD-95 shRNA knockdown did not prevent CRFR1-mediated enhancement of 5-HT2AR signaling. In conclusion, we have identified and characterized a novel functional relationship between CRFR1 and PSD-95 that may have implications in the design of new treatment strategies for mental illness.

KEYWORDS:

Arrestin; CRFR1; GPCR; PDZ; PSD-95; Trafficking

PMID:
26898829
DOI:
10.1016/j.cellsig.2016.02.013
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center