Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis.
Tetanus toxin is a potent neurotoxin that inhibits the release of neurotransmitters from presynaptic nerve endings. The mature toxin is composed of a heavy and a light chain that are linked via a disulfide bridge. After entry of tetanus toxin into the cytoplasm, the released light chain causes block of neurotransmitter release. Recent evidence suggests that the L-chain may act as a metalloendoprotease. Here we demonstrate that blockade of neurotransmission by tetanus toxin in isolated nerve terminals is associated with a selective proteolysis of synaptobrevin, an integral membrane protein of synaptic vesicles. No other proteins appear to be affected by tetanus toxin. In addition, recombinant light chain selectively cleaves synaptobrevin when incubated with purified synaptic vesicles. Our data suggest that cleavage of synaptobrevin is the molecular mechanism of tetanus toxin action.
Department of Pharmacology, Yale University Medical School, New Haven, CT 06510.
E
E
Link
L
L
Edelmann
J H
JH
Chou
T
T
Binz
S
S
Yamasaki
U
U
Eisel
M
M
Baumert
T C
TC
Südhof
H
H
Niemann
R
R
Jahn
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D007700:Kinetics; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D050683:R-SNARE Proteins; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013744:Tetanus Toxin / Q000494:pharmacology*
D005971:Glutamates; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D050683:R-SNARE Proteins; D013744:Tetanus Toxin; D018698:Glutamic Acid; D004533:Egtazic Acid; D002118:Calcium