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.

 亲爱的编辑，

单胺神经递质包括吲哚胺血清素 (5-HT)、儿茶酚胺多巴胺 (DA)、肾上腺素 (EP)、去甲肾上腺素 (NE) 和咪唑胺组胺 (HA)。 ¹这些神经递质对于情绪、唤醒、心境、奖赏、睡眠和记忆至关重要。 ² VMAT2 将单胺神经递质积累到突触小泡中进行储存并最终胞吐释放。最近的研究揭示了 5-HT 和 VMAT2 抑制剂的识别机制。 ^3,4,5然而，尚不完全了解 VMAT2 如何识别这些化学上多样化的神经递质以及帕金森病诱导剂 MPP ⁺ , ^6,7并表现出类似的运输活动。特别是，组胺被认为与不同的位点结合。 ⁸此外，VMAT2 的摄取活性是由液泡 H ⁺ -ATP 酶产生的跨膜质子电化学梯度驱动的。 ⁹然而，根据 VMAT2 与 5-HT 结合的当前结构，参与底物结合的质子化位点有所不同，被识别为 E312 ⁵或 D399。 ^3,4 VMAT2 中 5-HT 的结合姿势，无论是向内构象还是向外构象，都显着不同，胺基团从细胞质侧到腔侧发生 180 度翻转。 ^4,5因此，底物结合呈现不同的功能状态，并且确切的质子化位点需要进一步澄清。此外，另一个控制构象转变的质子化位点仍未确定。