Accession Number:

ADA180274

Title:

Mechanism of Action of Tetanus Toxin

Descriptive Note:

Annual rept. 1 Sep 1985-31 Aug 1986

Corporate Author:

NEW ENGLAND MEDICAL CENTER HOSPITAL BOSTON MA

Personal Author(s):

Report Date:

1986-10-01

Pagination or Media Count:

54.0

Abstract:

The mechanism by which tetanus toxin TT inhibits the release of neurotransmitters from neurons is unknown. Since secretion of lysosomal contents from monocytesmacrophages MOs appears to be similar to neurosecretion, we examined the effects of TT on MO secretion. In this system, TT-treated MOs caused a dose-dependent inhibition of lysozyme secretion in response to a calcium ionophore - A23187, Inhibited secretion was additionally demonstrated in TT-treated MOs when challenged with other soluble stimuli, phorbol myristate acetate PMA and formyl-leucyl-methionlyl-phenylalanine F-MetLeuPhe. Treatment with TT also caused inhibition of superoxide generation O2- in response to A23187, F-MetLeuPHe, PMA and opsonized zymosan. To explore the intracellular mechanism of inhibition of secretion by TT, cellular calcium homeostasis was examined. Using Quin-2 as a calcium probe for cytosolic calcium, we found that the inhibition of secretion by MO was not directly linked to calcium homeostasis, even though TT inhibits the rise of cytosolic calcium in response to low concentrations of ionomycin. In unstimulated MO, cytosolic protein kinase C PKC was inhibited in a dose-dependent manner. We have developed an in vivo mouse model of lethal generalized tetanus to examine the effect of TT on cellular kinases. We have demonstrated that incubation of PMN lysosomes with TT caused an augmented uptake of CA2.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE