RT Journal Article SR Electronic T1 Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP MOLPHARM-MR-2020-000089 DO 10.1124/molpharm.120.000089 A1 Karim S. Ibrahim A1 Khaled S. Abd-Elrahman A1 Salah El Mestikawy A1 Stephen SG Ferguson YR 2020 UL http://molpharm.aspetjournals.org/content/early/2020/07/13/molpharm.120.000089.abstract AB Crosstalk between both pre- and post-synaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions including synaptic plasticity and motor planning. Metabotropic glutamate receptor 5 (mGluR5) exhibits a promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders, as the consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) to ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5 and the dynamic crosstalk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions and cognition. Thus, aberrant signaling of the VGLUT3/mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson's disease, anxiety disorders and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3/mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. Significance Statement Vesicular glutamate receptor 3 (VGLUT3) machinery orchestrates glutamate release and its distribution overlaps with metabotropic glutamate receptor 5 (mGluR5) in regional brain circuitries including striatum, hippocampus and raphe nucleus. Therefore, VGLUT3/mGluR5 crosstalk can significantly influences both physiological and pathophysiological glutamatergic neurotransmission. Pathological signaling of the VGLUT3/mGluR5 axis is linked to Parkinson’s disease, anxiety disorders and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.