上海科技大学知识管理系统

["Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.","Author summary","Post-synaptic receptors are immobilized to form clusters at synapses. This process requires the participation of scaffolding proteins, and is thought to be of critical importance in central neurotransmission, ensuring the synaptic efficiency and fidelity. Here we report that two scaffold proteins, LIN-2/CASK and FRM-3/FARP, function as major synaptic organizers at C. elegans cholinergic neuromuscular junctions. LIN-2/CASK belongs to the MAGUK protein family and has been found to be important for cellular junctions. Knockout of lin-2 or frm-3 leads to severe defects in cholinergic synaptic transmission, with the mEPSC (miniature excitatory postsynaptic current) amplitude and synaptic localization of ionotropic acetylcholine receptors (AChRs) being dramatically reduced in lin-2 and frm-3 mutants. Conditional knockout of lin-2 or frm-3 in body wall muscles produced all phenotypes observed in the constitutive mutants, demonstrating that LIN-2/CASK and FRM-3/FARP function postsynaptically, regulating synaptic localization of AChRs. The function of LIN-2/CASK requires its SH3 and PDZ domains, which mediate interaction with AChRs and FRM-3. Collectively, our results have shown that scaffolding proteins LIN-2/CASK and FRM-3/FARP regulate postsynaptic AChRs, thereby promoting cholinergic synaptic transmission."]