title: Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function.
abstract: Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neurogenesis, neuritogenesis and synaptogenesis; however, the underlying molecular mechanism is not known. Here, we demonstrate orphan G-protein coupled receptor 110 (GPR110, ADGRF1) as the synaptamide receptor, mediating synaptamide-induced bioactivity in a cAMP-dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence tracing with chemical analogues of synaptamide reveal specific binding of GPR110 to synaptamide, which triggers cAMP production with low nM potency. Disruption of this binding or GPR110 gene knockout abolishes while GPR110 overexpression enhances synaptamide-induced bioactivity. GPR110 is highly expressed in fetal brains but rapidly decreases after birth. GPR110 knockout mice show significant deficits in object recognition and spatial memory. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and new insight into mechanisms by which DHA promotes brain development and function.
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Bill X
authors.initials: BX
authors.lastname: Huang
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: HeungSun
authors.initials: H
authors.lastname: Kwon
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Md Abdur
authors.initials: MA
authors.lastname: Rashid
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Desai
authors.affiliation: Chemistry Division of Preclinical Innovation, National Center for Advancement of Translational Sciences (NCATS), NIH, 9800 Medical Center Dr, Rockville, Maryland 20892, USA.
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.affiliation: Chemistry Division of Preclinical Innovation, National Center for Advancement of Translational Sciences (NCATS), NIH, 9800 Medical Center Dr, Rockville, Maryland 20892, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.affiliation: Laboratory of Molecular Signaling, NIAAA, NIH, 5625 Fishers Lane Room 3N-07, Bethesda, Maryland 20892-9410, USA.
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002460:Cell Line; D003071:Cognition / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D061251:Primary Cell Culture; D040901:Proteomics / Q000379:methods; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D021641:Recognition, Psychology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D065852:Spatial Memory / Q000502:physiology
chemical_list: C554449:ADGRF1 protein, human; C000628139:ADGRF1 protein, mouse; D063388:Endocannabinoids; C561061:N-docosahexaenoylethanolamide; D015513:Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D004281:Docosahexaenoic Acids; D000242:Cyclic AMP