Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function

Ji-Won Lee, Bill X. Huang, HeungSun Kwon, Md Abdur Rashid, Giorgi Kharebava, Abhishek Desai, Samarjit Patnaik, Juan Marugan and Hee-Yong Kim ()
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Ji-Won Lee: Laboratory of Molecular Signaling, NIAAA, NIH
Bill X. Huang: Laboratory of Molecular Signaling, NIAAA, NIH
HeungSun Kwon: Laboratory of Molecular Signaling, NIAAA, NIH
Md Abdur Rashid: Laboratory of Molecular Signaling, NIAAA, NIH
Giorgi Kharebava: Laboratory of Molecular Signaling, NIAAA, NIH
Abhishek Desai: Laboratory of Molecular Signaling, NIAAA, NIH
Samarjit Patnaik: National Center for Advancement of Translational Sciences (NCATS), NIH
Juan Marugan: National Center for Advancement of Translational Sciences (NCATS), NIH
Hee-Yong Kim: Laboratory of Molecular Signaling, NIAAA, NIH

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13123

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