Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes.
Clostridium neurotoxins produce inhibition of both basal and K(+)-evoked serotonin release in rat brain synaptosomes. To produce these effects, tetanus toxin (TeTx), as well as botulinum neurotoxin type A (BoNT/A), added to brain synaptosomes, must be incubated at 37 degrees C over a long interval (hours). This serotonin exocytosis inhibition was abolished with previous treatment with specific Zn2(+)-metalloprotease inhibitors. Nevertheless, a short incubation time produces different behavior of the indicated neurotoxins: TeTx significantly blocks the sodium-dependent, high-affinity serotonin uptake, whereas a small increase of this uptake was found with BoNT/A. Both Zn2(+)-metalloprotease active fragments, light chains of TeTx and BoNT/A, are unable to reproduce the block of the serotonin uptake, whereas the C-terminal portion of the TeTx heavy chain (Hc-TeTx), which binds specifically to the target tissue, inhibited the serotonin uptake in a dose-dependent manner. The IC50 of Hc-TeTx ranges from 0.62 to 2.08 nM. Binding of [3H]imipramine and [3H]serotonin did not change after toxin treatments, which indicates that these clostridium neurotoxins do not act on the serotonin high-affinity site at the serotonin transporter or at other serotonin high-affinity sites. These results could indicate that TeTx and Hc-TeTx bind to different targets than BoNT/A in the plasma membrane.
Najib
A
A
Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Pelliccioni
P
P
Gil
C
C
Aguilera
J
J
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013744:Tetanus Toxin / Q000737:chemistry / Q000494:pharmacology*
D009498:Neurotoxins; D010446:Peptide Fragments; D012702:Serotonin Antagonists; D013744:Tetanus Toxin; D012701:Serotonin; D019274:Botulinum Toxins, Type A