title: Neurotransmitter release regulated by a MALS-liprin-alpha presynaptic complex.
abstract: Synapses are highly specialized intercellular junctions organized by adhesive and scaffolding molecules that align presynaptic vesicular release with postsynaptic neurotransmitter receptors. The MALS/Veli-CASK-Mint-1 complex of PDZ proteins occurs on both sides of the synapse and has the potential to link transsynaptic adhesion molecules to the cytoskeleton. In this study, we purified the MALS protein complex from brain and found liprin-alpha as a major component. Liprin proteins organize the presynaptic active zone and regulate neurotransmitter release. Fittingly, mutant mice lacking all three MALS isoforms died perinatally with difficulty breathing and impaired excitatory synaptic transmission. Excitatory postsynaptic currents were dramatically reduced in autaptic cultures from MALS triple knockout mice due to a presynaptic deficit in vesicle cycling. These findings are consistent with a model whereby the MALS-CASK-liprin-alpha complex recruits components of the synaptic release machinery to adhesive proteins of the active zone.
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Olav
authors.initials: O
authors.lastname: Olsen
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Moore
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
authors.forename: Toshinari
authors.initials: T
authors.lastname: Kazuta
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trinidad
authors.forename: Fred W
authors.initials: FW
authors.lastname: Kauer
authors.forename: Michel
authors.initials: M
authors.lastname: Streuli
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.forename: Roger A
authors.initials: RA
authors.lastname: Nicoll
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D018390:Gene Targeting; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010316:Particle Size; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism*; D040901:Proteomics; D009435:Synaptic Transmission / Q000235:genetics; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C114670:Lin7a protein, mouse; C114672:Lin7c protein, mouse; D046911:Macromolecular Substances; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D033921:Vesicular Transport Proteins