The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction.
The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction.
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DOI：
10.1371/journal.pgen.1007263
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发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Babu K
中科院分区：
文献类型：
--
作者：
Thapliyal S;Vasudevan A;Dong Y;Bai J;Koushika SP;Babu K
梭哺乳动物钙合蛋白的elegans直系同源物CASY-1是一种进化上保守的I型跨膜蛋白，在神经系统中高度富集。哺乳动物的钙合蛋白在抑制性突触中强烈表达，但其在突触发育和功能中的作用仍然是难以捉摸的。在此，我们报道了CASY-1在调节C.神经肌肉接头（NMJ）。CASY-1的较短同种型; CASY-1B和CASY-1C，在GABA运动神经元中表达并发挥作用，在那里它们调节GABA神经传递。利用药理学、行为学、电生理学、光遗传学和成像方法，我们确定GABA释放在Casy-1突变体的NMJ处受到损害。此外，我们证明，CASY-1是需要通过与SV马达蛋白，GABA-104/KIF 1A的可能的相互作用来调节GABA能突触囊泡（SV）前体的运输。这项研究提出了一个可能的进化保守的模型，调节GABA突触功能的钙合蛋白。GABA在脊椎动物和无脊椎动物的神经系统中作为一种主要的抑制性神经递质。尽管在一些神经系统疾病中GABA信号可能失调，但我们对调节GABA能突触传递的遗传因子的理解才刚刚开始发展。在这里，我们确定了一个细胞粘附分子，CASY-1，在调节GABA信号在C。秀丽隐杆线虫NMJ.我们发现casy-1的突变体减少了突触处GABA囊泡的数量，导致突触前GABA能运动神经元释放的GABA减少。此外，我们表明，casy-1基因的较短的同种型，casy-1b和casy-1c，携带一个潜在的驱动蛋白运动结合域负责维持GABA能信号在突触。我们显示了CASY-1亚型与介导GABA能突触囊泡前体向突触的运输的JNK-104/KIF 1A马达蛋白的C末端的新型相互作用，从而维持NMJ处的正常抑制性信号传导。
The C. elegans ortholog of mammalian calsyntenins, CASY-1, is an evolutionarily conserved type-I transmembrane protein that is highly enriched in the nervous system. Mammalian calsyntenins are strongly expressed at inhibitory synapses, but their role in synapse development and function is still elusive. Here, we report a crucial role for CASY-1 in regulating GABAergic synaptic transmission at the C. elegans neuromuscular junction (NMJ). The shorter isoforms of CASY-1; CASY-1B and CASY-1C, express and function in GABA motor neurons where they regulate GABA neurotransmission. Using pharmacological, behavioral, electrophysiological, optogenetic and imaging approaches we establish that GABA release is compromised at the NMJ in casy-1 mutants. Further, we demonstrate that CASY-1 is required to modulate the transport of GABAergic synaptic vesicle (SV) precursors through a possible interaction with the SV motor protein, UNC-104/KIF1A. This study proposes a possible evolutionarily conserved model for the regulation of GABA synaptic functioning by calsyntenins. GABA acts as a major inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems. Despite the potential deregulation of GABA signaling in several neurological disorders, our understanding of the genetic factors that regulate GABAergic synaptic transmission has just started to evolve. Here, we identify a role for a cell adhesion molecule, CASY-1, in regulating GABA signaling at the C. elegans NMJ. We show that the mutants in casy-1 have reduced number of GABA vesicles at the synapse resulting in less GABA release from the presynaptic GABAergic motor neurons. Further, we show that the shorter isoforms of the casy-1 gene; casy-1b and casy-1c that carry a potential kinesin-motor binding domain are responsible for maintaining GABAergic signaling at the synapse. We show a novel interaction of the CASY-1 isoforms with the C- terminal of the UNC-104/KIF1A motor protein that mediates the trafficking of GABAergic synaptic vesicle precursors to the synapse, thus maintaining normal inhibitory signaling at the NMJ.
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