Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.
Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.
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DOI：
10.1016/j.neuron.2016.03.026
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发表时间：
2016-05-18
期刊：
影响因子：
16.2
通讯作者：
Edwards RH
中科院分区：
文献类型：
--
作者：
Eriksen J;Chang R;McGregor M;Silm K;Suzuki T;Edwards RH
突触传递的量子性质需要一种将神经递质转运到突触小泡中而不促进跨质膜的非小泡流出的机制。事实上，大多数经典递质的囊泡运输涉及 H+ 交换机制，该机制限制流向酸性膜（例如突触囊泡）。然而，主要兴奋性递质谷氨酸的囊泡运输主要取决于膜电位，这将驱动非囊泡外流，并且质子的作用尚不清楚。采用电生理学来记录与囊泡谷氨酸转运蛋白（VGLUT）相关的电流，我们描述了由腔质子和氯离子门控并支持谷氨酸摄取的氯离子电导。腔质子和氯不是以化学计量耦合到谷氨酸通量，而是以变构方式激活囊泡谷氨酸转运。质子门控用于抑制质膜上大量的非囊泡谷氨酸流出，从而限制突触囊泡的 VGLUT 活性。
The quantal nature of synaptic transmission requires a mechanism to transport neurotransmitter into synaptic vesicles without promoting non-vesicular efflux across the plasma membrane. Indeed, the vesicular transport of most classical transmitters involves a mechanism of H+ exchange which restricts flux to acidic membranes such as synaptic vesicles. However, vesicular transport of the principal excitatory transmitter glutamate depends primarily on membrane potential, which would drive non-vesicular efflux, and the role of protons is unclear. Adapting electrophysiology to record currents associated with the vesicular glutamate transporters (VGLUTs), we characterize a chloride conductance that is gated by lumenal protons and chloride and supports glutamate uptake. Rather than coupling stoichiometrically to glutamate flux, lumenal protons and chloride allosterically activate vesicular glutamate transport. Gating by protons serves to inhibit what would otherwise be substantial non-vesicular glutamate efflux at the plasma membrane, thereby restricting VGLUT activity to synaptic vesicles.