C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and UNC-40/DCC Recruitment

• Published in: Neuron (Cambridge, Mass.) Vol. 86; no. 6; pp. 1407 - 1419
• Main Authors: Tu, Haijun, Pinan-Lucarré, Bérangère, Ji, Tingting, Jospin, Maelle, Bessereau, Jean-Louis
• Format: Journal Article
• Language: English
• Published: United States 17.06.2015
• Subjects: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Electric Stimulation; GABAergic Neurons - physiology; HEK293 Cells; Humans; Luminescent Proteins - genetics; Membrane Potentials - drug effects; Membrane Potentials - genetics; Muscle Cells - metabolism; Mutation - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuromuscular Junction - metabolism; Protein Binding - genetics; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1097-4199
• DOI: 10.1016/j.neuron.2015.05.013

Positioning type A GABA receptors (GABA(A)Rs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD-4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABA(A)Rs through the synaptic adhesion molecule neuroligin (NLG-1) and the netrin receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABA(A)R content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABA(A)Rs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved.