biostudies-literatureWang XCanadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of CanadaUniversity of Toronto Undergraduate Research Fund; University of Toronto Excellence Award in Natural Sciences and EngineeringCanadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)NIDA NIH HHSNIEHS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | NIH | Center for Information TechnologyU.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health)Parkinson's FoundationParkinson's Foundation (Parkinson's Foundation, Inc.)Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)U.S. Department of Health & Human Services | National Institutes of HealthGouvernement du Canada | Canadian Institutes of Health Research1783-1791https://www.ebi.ac.uk/biostudies/studies/S-EPMC11399425biostudies-literatureUnknown49(11)Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also dNeuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyTricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants.PMC11399425PF-PRF-933478RGPIN-2018-06409407961R01 ES023839U18 DA052498U18DA052498R01ES023839391676T32 ES007322T32ES007322Stove SIWilliams EQLipina TVSalahpour AMiller GWMarmouzi IBucher MLRamsey AJWang XYan YFinnie PSBfalseTricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants.Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also d2024-01-01T00:00:00Z2024 Oct2026-06-03T03:44:40.813Z2025-04-05T23:44:31.281ZS-EPMC113994253906043610.1038/s41386-024-01914-2