The Regulatory Role of Syntaxin 1 N-terminal Conformation in Vesicle Priming and Exocytosis
Die Regulation der Vesikelreifung und -Freisetzung durch Syntaxin 1
von Jong-Cheol Rah
Datum der mündl. Prüfung:2004-11-02
Erschienen:2004-12-16
Betreuer:Prof. Dr. Erwin Neher
Gutachter:Prof. Dr. Dietrich Gradmann
Gutachter:Prof. Dr. Ernst A. Wimmer
Gutachter:Prof. Dr. Hans-Joachim Fritz
Dateien
Name:rah.pdf
Size:7.83Mb
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Description:Dissertation
Zusammenfassung
Englisch
During vesicle priming at the central synapse, Syntaxin 1, together with SNAP25 and Synaptobrevin, assemble into the synaptic SNARE complex. The formation of SNARE complex is thought to provide the energy needed that enables vesicle exocytosis during Ca2+ triggering step at the presynapse. Among the SNARE proteins, Syntaxin 1 is thought to play a special role in regulating the rate of SNARE assembly by adopting two conformations; a closed autoinhibitory conformation in which core complex domain is hindered by N-terminal Habc domain, and an open conformation in which the SNARE motif of syntaxin is open and ready to interact with the other SNAREs.In the present study we examined the role of the conformational switch of syntaxin 1 by analyzing synaptic properties of genetically modified mice expressing a mutation that leaves syntaxin 1 in a constitutively open conformation. In cultured hippocampal neurons, the mutation led to a significant increase in the rate of vesicle priming, supporting the hypothesis that syntaxin 1 regulates vesicle priming during the SNARE complex assembly process. Surprisingly, we also found that the mutation led to an increase in synaptic release probability, suggesting that the conformation of syntaxin 1 also regulates vesicle fusion by reducing the energy barrier of vesicle fusion to the plasma membrane. Our data support the idea that the SNARE complex member syntaxin 1 and its individual conformations are crucial regulators of the efficacy and short-term plasticity of synaptic transmission.
Keywords: hippocampus; CNS; neuron; neurotransmitter; exocytosis; SNARE; syntaxin 1A; conformation
Weitere Sprachen
During vesicle priming at the central synapse,
Syntaxin 1, together with SNAP25 and Synaptobrevin,
assemble into the synaptic SNARE complex. The formation
of SNARE complex is thought to provide the energy
needed that enables vesicle exocytosis during Ca2+
triggering step at the presynapse. Among the SNARE
proteins, Syntaxin 1 is thought to play a special role
in regulating the rate of SNARE assembly by adopting
two conformations; a closed autoinhibitory conformation
in which core complex domain is hindered by N-terminal
Habc domain, and an open conformation in which the
SNARE motif of syntaxin is open and ready to interact
with the other SNAREs.In the present study we examined the role of the
conformational switch of syntaxin 1 by analyzing
synaptic properties of genetically modified mice
expressing a mutation that leaves syntaxin 1 in a
constitutively open conformation. In cultured
hippocampal neurons, the mutation led to a significant
increase in the rate of vesicle priming, supporting the
hypothesis that syntaxin 1 regulates vesicle priming
during the SNARE complex assembly process.
Surprisingly, we also found that the mutation led to an
increase in synaptic release probability, suggesting
that the conformation of syntaxin 1 also regulates
vesicle fusion by reducing the energy barrier of
vesicle fusion to the plasma membrane. Our data support
the idea that the SNARE complex member syntaxin 1 and
its individual conformations are crucial regulators of
the efficacy and short-term plasticity of synaptic
transmission.
Schlagwörter: hippocampus; CNS; neuron; neurotransmitter; exocytosis; SNARE; syntaxin 1A; conformation