PSD-95 regulates CRFR1 localization, trafficking and ?-arrestin2 recruitment.
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 ?-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.
Mesh Terms:
Animals, Cells, Cultured, Cyclic AMP, Disks Large Homolog 4 Protein, Endocytosis, Extracellular Signal-Regulated MAP Kinases, Guanylate Kinases, HEK293 Cells, Humans, Membrane Proteins, Mice, Post-Synaptic Density, Protein Interaction Domains and Motifs, Protein Transport, Receptors, Corticotropin-Releasing Hormone, Signal Transduction, beta-Arrestin 2
Animals, Cells, Cultured, Cyclic AMP, Disks Large Homolog 4 Protein, Endocytosis, Extracellular Signal-Regulated MAP Kinases, Guanylate Kinases, HEK293 Cells, Humans, Membrane Proteins, Mice, Post-Synaptic Density, Protein Interaction Domains and Motifs, Protein Transport, Receptors, Corticotropin-Releasing Hormone, Signal Transduction, beta-Arrestin 2
Cell. Signal.
Date: May. 01, 2016
PubMed ID: 26898829
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