Mechanisms of vesicular monoamine transporter 2 modulation by amphetamines and lobeline.

Cryo-EM structures of human VMAT2 show that AMPH, METH, MDMA, and MDA occupy the substrate-binding site as substrates, while lobeline binds in a dual mode that locks a lumen-facing conformation.

• Why it matters: ATSs strongly stimulate motivation, movement, and addiction, yet how they bind to and regulate VMAT2 is elusive. Understanding VMAT2 modulation is key to explaining monoaminergic disruption.
• What they did: The authors determined cryo-EM structures of human VMAT2 with four ATSs (AMPH, METH, MDMA, and MDA) and lobeline, and performed a dopamine release assay. They assessed how lobeline affects AMPH-induced dopamine release by modulating VMAT2 and DAT.
• The result: ATSs mimic monoamines and redistribute vesicular monoamine pools to cytosolic pools, whereas lobeline inhibits monoamine and ATS uptake by dual-binding and lumen-facing locking. Lobeline regulates AMPH-induced dopamine release through effects on both VMAT2 and DAT.