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The Journal of Neuroscience, December 1, 2001, 21(23):9142-9150
Targeted Mutations in the Syntaxin H3 Domain Specifically Disrupt SNARE Complex Function in Synaptic Transmission
Tim Fergestad1, Mark N. Wu2, Karen L. Schulze3, Thomas E. Lloyd2, Hugo J. Bellen2, 3, 4, and Kendal Broadie1 1 Department of Biology, University of Utah, Salt Lake City, Utah 84112-0840, and Departments of 2 Molecular and Cellular Biology and 3 Molecular and Human Genetics, 4 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030
The cytoplasmic H3 helical domain of syntaxin is implicated in numerous protein-protein interactions required for the assembly and stability of the SNARE complex mediating vesicular fusion at the synapse. Two specific hydrophobic residues (Ala-240, Val-244) in H3 layers 4 and 5 of mammalian syntaxin1A have been suggested to be involved in SNARE complex stability and required for the inhibitory effects of syntaxin on N-type calcium channels. We have generated the equivalent double point mutations in Drosophila syntaxin1A (A243V, V247A; syx4 mutant) to examine their significance in synaptic transmission in vivo. The syx4 mutant animals are embryonic lethal and display severely impaired neuronal secretion, although non-neuronal secretion appears normal. Synaptic transmission is nearly abolished, with residual transmission delayed, highly variable, and nonsynchronous, strongly reminiscent of transmission in null synaptotagmin I mutants. However, the syx4 mutants show no alterations in synaptic protein levels in vivo or syntaxin partner binding interactions in vitro. Rather, syx4 mutant animals have severely impaired hypertonic saline response in vivo, an assay indicating loss of fusion-competent synaptic vesicles, and in vitro SNARE complexes containing Syx4 protein have significantly compromised stability. These data suggest that the same residues required for syntaxin-mediated calcium channel inhibition are required for the generation of fusion-competent vesicles in a neuronal-specific mechanism acting at synapses.
Key words: Drosophila; SNARE complex; core complex; syntaxin; synaptotagmin; calcium channel
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239142-09$05.00/0
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