VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior.
VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior.
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DOI：
10.1371/journal.pgen.1009375
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Juo P
中科院分区：
文献类型：
--
作者：
Luth ES;Hodul M;Rennich BJ;Riccio C;Hofer J;Markoja K;Juo P
多种细胞内运输途径有助于调节突触处的 AMPA 受体 (AMPAR) 水平和控制突触强度。虽然人们对这些细胞内转运途径已经了解很多，但主要的挑战是了解细胞外因子（例如生长因子、神经肽和激素）如何影响特定的 AMPAR 转运途径以改变突触功能和行为。在这里，我们确定了分泌配体 PVF-1 及其同源 VEGF 受体同源物 VER-1 和 VER-4，作为线虫中谷氨酸信号传导的调节剂。 ver-1、ver-4 或 pvf-1 的功能缺失突变会导致细胞表面 AMPAR GLR-1 水平降低和谷氨酸能行为缺陷。救援实验表明，PVF-1 在肌肉中表达并释放，而 VER 在表达 GLR-1 的神经元中发挥作用，调节 GLR-1 的表面水平和谷氨酸能行为。此外，在没有 pvf-1 的情况下，ver-4 无法挽救谷氨酸能行为，这表明 VER 功能需要内源性 PVF-1。 pvf-1 拯救转基因的诱导表达表明 PVF-1 可以在成熟神经系统中发挥作用，调节 GLR-1 信号传导。遗传双突变体分析表明，VER 与 VPS-35/retromer 回收复合物一起作用，促进细胞表面 GLR-1 水平。我们的数据支持遗传模型，PVF-1/VER 信号传导与逆转录酶共同作用，促进 GLR-1 的回收和细胞表面水平的控制行为。感觉、行为和认知都取决于称为突触的神经元连接的正常功能。使用神经递质谷氨酸在神经细胞之间发出信号的突触是我们大脑中最丰富的类型。突触前神经元释放谷氨酸，激活突触后神经元上的谷氨酸受体。谷氨酸突触功能障碍会导致多种神经系统疾病，而改变其强度（部分是通过改变突触后细胞表面的谷氨酸受体数量）提供了学习和记忆的细胞基础。关于其他细胞类型释放的因子如何影响突触通讯，还有很多东西有待了解。我们利用被设计到秀丽隐杆线虫特定感觉神经元中的光激活分子开关来触发依赖于谷氨酸突触的行为反射。利用这种行为，我们确定了称为 VER-1 和 VER-4 的蛋白质对于谷氨酸突触功能很重要。我们发现，缺少这些 VER 蛋白或其激活剂 PVF-1 的线虫突触后表面的谷氨酸受体水平降低，并且谷氨酸依赖性行为出现缺陷。我们的结果表明，肌肉 PVF-1 和神经元 VER 之间的组织间串扰对于控制细胞表面谷氨酸受体的数量、强大的神经元通讯和行为反应非常重要。
Several intracellular trafficking pathways contribute to the regulation of AMPA receptor (AMPAR) levels at synapses and the control of synaptic strength. While much has been learned about these intracellular trafficking pathways, a major challenge is to understand how extracellular factors, such as growth factors, neuropeptides and hormones, impinge on specific AMPAR trafficking pathways to alter synaptic function and behavior. Here, we identify the secreted ligand PVF-1 and its cognate VEGF receptor homologs, VER-1 and VER-4, as regulators of glutamate signaling in C. elegans. Loss of function mutations in ver-1, ver-4, or pvf-1, result in decreased cell surface levels of the AMPAR GLR-1 and defects in glutamatergic behavior. Rescue experiments indicate that PVF-1 is expressed and released from muscle, whereas the VERs function in GLR-1-expressing neurons to regulate surface levels of GLR-1 and glutamatergic behavior. Additionally, ver-4 is unable to rescue glutamatergic behavior in the absence of pvf-1, suggesting that VER function requires endogenous PVF-1. Inducible expression of a pvf-1 rescuing transgene suggests that PVF-1 can function in the mature nervous system to regulate GLR-1 signaling. Genetic double mutant analysis suggests that the VERs act together with the VPS-35/retromer recycling complex to promote cell surface levels of GLR-1. Our data support a genetic model whereby PVF-1/VER signaling acts with retromer to promote recycling and cell surface levels of GLR-1 to control behavior. Sensation, behavior, and cognition all depend on the proper function of neuronal connections called synapses. Synapses that use the neurotransmitter glutamate to signal between nerve cells are the most abundant type in our brain. Presynaptic neurons release glutamate, which activates glutamate receptors on postsynaptic neurons. Dysfunction of glutamate synapses leads to several neurological disorders, and changing their strength–in part by altering glutamate receptors numbers on the surface of the postsynaptic cell—provides the cellular basis of learning and memory. Much remains to be learned about how factors released from other cell types affects synaptic communication. We took advantage of light-activated molecular switches engineered into specific sensory neurons of C. elegans worms to trigger a behavioral reflex that depends on glutamate synapses. Using this behavior, we identified proteins called VER-1 and VER-4 as important for glutamate synapse function. We found that worms missing these VER proteins or their activator PVF-1 have reduced levels of glutamate receptors at the postsynaptic surface and defects in glutamate-dependent behaviors. Our results suggest that inter-tissue cross-talk between muscle PVF-1 and neuronal VERs is important for controlling the number of glutamate receptors at the cell surface, robust neuronal communication and behavioral responses.
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