RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 41; pp. 11615 - 11620
• Main Authors: Grauel, M. Katharina, Maglione, Marta, Reddy-Alla, Suneel, Willmes, Claudia G., Brockmann, Marisa M., Trimbuch, Thorsten, Rosenmund, Tanja, Pangalos, Maria, Vardar, Gülçin, Stumpf, Alexander, Walter, Alexander M., Rost, Benjamin R., Eickholt, Britta J., Haucke, Volker, Schmitz, Dietmar, Sigrist, Stephan J., Rosenmund, Christian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.10.2016
• Subjects: Action Potentials; Animals; Biological Sciences; Calcium; Calcium - metabolism; Calcium Channels - metabolism; Cells, Cultured; Electrophysiological Phenomena; Female; Gene Deletion; Gene Expression; Gene Targeting; Genetic Loci; Genotype & phenotype; Hippocampus - metabolism; Male; Mice; Mice, Knockout; Molecules; Neurons; Neurons - metabolism; Neurotransmitters; Phenotype; Protein Transport; Proteins; Synapses - metabolism; Synaptic Transmission - genetics; Synaptic Vesicles - metabolism; calcium channel coupling; RIM-BP2; active zone structure; release probability; short-term plasticity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1605256113

The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (Cavs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2–deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in Cav2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.