Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10815908 | Cellular Signalling | 2015 | 32 Pages |
Abstract
Orexin and dynorphin are co-expressed in the same synaptic vesicles of hypothalamic neurons and play opposing roles in cocaine self-administration, brain stimulation reward, and impulsivity in ventral tegmental area (VTA), where dopamine neurons express both OX1R and KORs. However, detailed mechanisms of how the coreleased peptides and both receptors fine-tune their signalings and physiological/behavioral effects together remain unclear. Here we explore the possibility of heterodimerization between OX1R and KOR and reveal novel signal transduction mechanisms. First, we demonstrated co-expression of OX1R and KOR in rat hippocampal neurons by single-cell PCR. Furthermore, heterodimerization between OX1R and KOR was examined using bioluminescence and fluorescence resonance energy transfer (BRET and FRET). Our data revealed that human OX1R and KOR heterodimerize, and this heterodimer associates with Gαs, leading to increased protein kinase A (PKA) signaling pathway activity, including upregulation of intracellular cAMP levels and cAMP-response element (CRE) luciferase reporter activity, resulting in increased cAMP-response element binding protein (CREB) phosphorylation. These results support the view that OX1R and KOR heterodimerization might have an anti-depressive role.
Keywords
CREBYFPRlucOX1RCUMSGPCRpKaCFPBioluminescence resonance energy transfer (BRET)G-protein-coupled receptorG-protein-coupled receptor (GPCR)Förster resonance energy transfer (FRET)Fluorescence resonance energy transferbioluminescence resonance energy transferFRETBRETELISAEnzyme-linked immunosorbent assayHeterodimerizationKORcAMP-response element binding proteinyellow fluorescent proteincyan fluorescent proteinprotein kinase Akappa opioid receptor
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Authors
Jing Chen, Rumin Zhang, Xiaoyu Chen, Chunmei Wang, Xin Cai, Haiqing Liu, Yunlu Jiang, Chuanxin Liu, Bo Bai,