title: RIM-BPs Mediate Tight Coupling of Action Potentials to Ca(2+)-Triggered Neurotransmitter Release.
abstract: Ultrafast neurotransmitter release requires tight colocalization of voltage-gated Ca(2+) channels with primed, release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels. In Drosophila, deletion of RIM-BPs dramatically reduces neurotransmitter release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast release in mammalian synapses without being a central component of the machinery itself.
authors.affiliation: Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: claudioa@stanford.edu.
authors.forename: Claudio
authors.initials: C
authors.lastname: Acuna
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aneysis
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: tcs1@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020692:rab3 GTP-Binding Proteins / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D002118:Calcium; D020864:Calcium Channels, N-Type; D018377:Neurotransmitter Agents; D020692:rab3 GTP-Binding Proteins; C512841:Abca4 protein, mouse; C500545:CACNA1B protein, human; C475524:Rim2 protein, mouse