Neurotransmitter release regulated by a MALS-liprin-alpha presynaptic complex.
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.
Olsen
Olav
O
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Moore
Kimberly A
KA
Fukata
Masaki
M
Kazuta
Toshinari
T
Trinidad
Jonathan C
JC
Kauer
Fred W
FW
Streuli
Michel
M
Misawa
Hidemi
H
Burlingame
Alma L
AL
Nicoll
Roger A
RA
Bredt
David S
DS
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
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