Department of Biological Sciences, Delaware State University, Dover, Delaware.
Delaware Biotechnology Institute, University of Delaware, Newark, Delaware.
Synapse. 2020 Jan;74(1):e22131. doi: 10.1002/syn.22131. Epub 2019 Sep 23.
Mechanisms of synaptic vesicular fusion and neurotransmitter clearance are highly controlled processes whose finely-tuned regulation is critical for neural function. This modulation has been suggested to involve pre-synaptic auto-receptors; however, their underlying mechanisms of action remain unclear. Previous studies with the well-defined C. elegans nervous system have used functional imaging to implicate acid sensing ion channels (ASIC-1) to describe synaptic vesicle fusion dynamics within its eight dopaminergic neurons. Implementing a similar imaging approach with a pH-sensitive fluorescent reporter and fluorescence resonance after photobleaching (FRAP), we analyzed dynamic imaging data collected from individual synaptic termini in live animals. We present evidence that constitutive fusion of neurotransmitter vesicles on dopaminergic synaptic termini is modulated through DOP-2 auto-receptors via a negative feedback loop. Integrating our previous results showing the role of ASIC-1 in a positive feedback loop, we also put forth an updated model for synaptic vesicle fusion in which, along with DAT-1 and ASIC-1, the dopamine auto-receptor DOP-2 lies at a modulatory hub at dopaminergic synapses. Our findings are of potential broader significance as similar mechanisms are likely to be used by auto-receptors for other small molecule neurotransmitters across species.
突触囊泡融合和神经递质清除的机制是高度受控的过程，其精细调节对于神经功能至关重要。这种调节被认为涉及到突触前自身受体;然而，其作用的潜在机制仍不清楚。以前使用定义明确的秀丽隐杆线虫神经系统的研究已经使用功能成像来暗示酸感应离子通道（ASIC-1）来描述其八个多巴胺能神经元内的突触囊泡融合动力学。我们使用 pH 敏感荧光报告器和荧光共振后光漂白 (FRAP) 实施了类似的成像方法，从活体动物的单个突触末端收集动态成像数据。我们提供的证据表明，多巴胺能突触末端神经递质囊泡的组成型融合是通过 DOP-2 自身受体通过负反馈环调节的。整合我们之前显示 ASIC-1 在正反馈环中作用的结果，我们还提出了一个更新的突触囊泡融合模型，其中多巴胺自身受体 DOP-2 与 DAT-1 和 ASIC-1 一起位于多巴胺能突触的调节枢纽上。我们的发现具有潜在的更广泛意义，因为类似的机制可能被自身受体用于其他物种的其他小分子神经递质。
