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Published 26 September 2005. doi:10.1083/jcb.200503011
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 7, 1127-1134
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Article

Neurotransmitter release regulated by a MALS–liprin-{alpha} presynaptic complex



Olav Olsen1, Kimberly A. Moore2, Masaki Fukata1, Toshinari Kazuta1, Jonathan C. Trinidad3, Fred W. Kauer1, Michel Streuli4, Hidemi Misawa5, Alma L. Burlingame3, Roger A. Nicoll1,2, and David S. Bredt1

1 Department of Physiology, University of California, San Francisco, San Francisco, CA 94143
2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143
3 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143
4 ImmunoGen, Inc., Cambridge, MA 02139
5 Department of Neurology, Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan

Correspondence to David S. Bredt: bredt{at}itsa.ucsf.edu

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.

Abbreviations used in this paper: AMPA, {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; CaMK, CAM kinase; DIV, days in vitro; EPSC, excitatory postsynaptic current; MS, mass spectrometry; NMDA, N-methyl-D-aspartate; PSD, postsynaptic density; SAM, sterile {alpha} motif; TKO, triple knockout; WT, wild type.


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