Structural snapshots of human VMAT2 reveal insights into substrate recognition and proton coupling mechanism

Dear Editor,

Monoamine neurotransmitters include indolamine serotonin (5-HT), the catecholamine dopamine (DA), epinephrine (EP), norepinephrine (NE), and imidazolamine histamine (HA).¹ These neurotransmitters are critical in emotion, arousal, mood, reward, sleep, and memory.² VMAT2 accumulates monoamine neurotransmitters into synaptic vesicles for storage and eventual exocytotic release. Recent studies have shed light on the recognition mechanisms of 5-HT and VMAT2 inhibitors.^3,4,5 However, it is not yet fully understood how VMAT2 recognizes these chemically diverse neurotransmitters, as well as a parkinsonism-inducer MPP⁺,^6,7 and demonstrates comparable transport activities. Especially, the histamine is thought to bind to a different site.⁸ Moreover, the uptake activity of VMAT2 is driven by the transmembrane proton electrochemical gradient generated by vacuolar H⁺-ATPase.⁹ However, based on the current structures of VMAT2 bound to 5-HT, the protonation sites involved in substrate binding differ and are recognized either as E312⁵ or D399.^3,4 The binding poses of 5-HT within VMAT2, in both inward-facing and outward-facing conformations, are dramatically different, with the amine group undergoing a 180-degree flip from the cytosol side to the lumen side.^4,5 Therefore, the substrate binding poses in different functional states and the exact protonation site require further clarification. In addition, another protonation site governing the conformational transition remains undefined.

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