Manning Abbey, Mendelson Benjamin Z, Bender Philip T R, Bainer Kaitlin, Ruby Rayli, Shifflett Victoria R, Dariano Donald F, Webb Bradley A, Geldenhuys Werner J, Anderson Charles T
Departments of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, West Virginia 26506.
Biochemistry and Molecular Medicine, West Virginia University School of Medicine, Morgantown, West Virginia 26506.
J Neurosci. 2025 Mar 26;45(13):e2067242025. doi: 10.1523/JNEUROSCI.2067-24.2025.
Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein zinc transporter 3 (ZnT3). Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses. We identify small-molecule compounds that antagonize the function of ZIP12 in heterologous expression systems, and we use one of these compounds, ZIP12 modulator 8, to increase the concentration of ZnT3-dependent zinc at synapses in the brain of male and female mice to inhibit the activity of neuronal AMPA and NMDA glutamate receptors. These results identify a cellular mechanism and provide a pharmacological toolbox to target the molecular machinery that supports the actions of synaptic zinc in the brain.
突触释放的锌是一种神经元信号系统，它源于突触前囊泡锌转运蛋白锌转运体3（ZnT3）的作用。调节锌在突触处作用的机制对于大脑中突触信号传导的许多方面都非常重要。在这里，我们确定星形胶质细胞锌转运蛋白ZIP12是一种有助于清除皮质突触处锌的候选机制。我们鉴定出在异源表达系统中拮抗ZIP12功能的小分子化合物，并使用其中一种化合物ZIP12调节剂8来增加雄性和雌性小鼠大脑突触处依赖ZnT3的锌浓度，以抑制神经元AMPA和NMDA谷氨酸受体的活性。这些结果确定了一种细胞机制，并提供了一个药理学工具箱，以靶向支持大脑中突触锌作用的分子机制。
