title: Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Gαs-mediated mechanism.
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.
authors: Division of Translational and Systems Medicine, Warwick Medical School, University of Warwick, Coventry, UK; Neurobiology Institute, Jining Medical University, Jining 272067, PR China. Electronic address: Jing.Chen@warwick.ac.uk.
authors: Jing
authors: J
authors: Chen
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
authors: Rumin
authors: R
authors: Zhang
authors: Department of Physiology, Taishan Medical University, Taian 271000, PR China.
authors: Xiaoyu
authors: X
authors: Chen
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
authors: Chunmei
authors: C
authors: Wang
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
authors: Xin
authors: X
authors: Cai
authors: Department of Physiology, Taishan Medical University, Taian 271000, PR China.
authors: Haiqing
authors: H
authors: Liu
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
authors: Yunlu
authors: Y
authors: Jiang
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China.
authors: Chuanxin
authors: C
authors: Liu
authors: Neurobiology Institute, Jining Medical University, Jining 272067, PR China. Electronic address: bbai@mail.jnmc.edu.cn.
authors: Bo
authors: B
authors: Bai
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D064446:Orexin Receptors; D000068797:Orexins; D017473:Receptors, Opioid, kappa; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium
keywords: Bioluminescence resonance energy transfer (BRET); Förster resonance energy transfer (FRET); G-protein-coupled receptor (GPCR); Heterodimerization; Kappa opioid receptor (KOR); Orexin (hypocretin) receptor 1 (OX1R)