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.
Highlights
Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development
We observed that synaptamide promotes neurite growth and synaptogenesis in hippocampal neurons[10] and induces neurogenic differentiation[11] and cyclic adenosine monophosphate/protein kinase A signalling at a low nM range in NSCs21
We discovered that synaptamide is an endogenous ligand to the orphan GPR110, triggering Gas-coupled cyclic adenosine monophosphate (cAMP) production
Summary
Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. DHA-derived neurogenic, neuritogenic and synaptogenic bioactivity is considerably enhanced when fatty acid amide hydrolase is inhibited[10,11] These findings suggest that synaptamide is a principal mediator for the observed bioactivity of DHA, most likely involving a specific target receptor. In this paper, using a chemical and proteomic strategy altogether with molecular and cellular characterization, we identified orphan GPR110 (ADGRF1), a member of the less-known aGPCRs, as the functional synaptamide receptor mediating synaptamide-induced neurite growth and synaptogenesis in cortical neurons and neurogenic differentiation of NSCs. We suggest that synaptamide-activated GPR110 signalling is an important molecular mechanism for the neurodevelopmental actions of omega-3 fatty acids
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