Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Manauli, Punjab, India.
Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India.
PLoS Genet. 2018 Mar 12;14(3):e1007263. doi: 10.1371/journal.pgen.1007263. eCollection 2018 Mar.
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.
秀丽隐杆线虫的钙结合蛋白同系物 CASY-1 是一种高度保守的 I 型跨膜蛋白，在神经系统中高度富集。哺乳动物的钙结合蛋白同系物在抑制性突触中强烈表达，但它们在突触发育和功能中的作用仍不清楚。在这里，我们报告了 CASY-1 在调节秀丽隐杆线虫神经肌肉接头（NMJ）上 GABA 能突触传递中的关键作用。较短的 CASY-1 异构体；CASY-1B 和 CASY-1C，在 GABA 运动神经元中表达和发挥作用，在那里它们调节 GABA 神经递质传递。我们使用药理学、行为学、电生理学、光遗传学和成像方法证明，在 casy-1 突变体中，NMJ 处的 GABA 释放受损。此外，我们证明 CASY-1 是通过与 SV 运动蛋白 UNC-104/KIF1A 的可能相互作用来调节 GABA 能突触囊泡（SV）前体的运输所必需的。这项研究提出了一个可能的进化保守模型，用于钙结合蛋白同系物对 GABA 突触功能的调节。
