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TeTx site of action

Figure 6 Sites of action of TeTx and BoNTs. This figure has three main features:

1. Reflex arc. Mechanism for inhibiting the antagonists to a muscle contracting in response to stretch. Muscles are reciprocally innervated with sensory and motor neurons, although for clarity this is shown only for the protagonist muscle. On stretch, the stretch receptors generate an impulse which is transmitted along the afferent sensory (S) neuron (SP) of the protagonist muscle. This SP enters the spinal cord by the dorsal root and synapses with the motor neuron (MP) supplying the protagonist muscle and with an interneuron (I) which in turn synapses with the motor neuron (MA) supplying the antagonist muscle; the efferent motor neurons leave the spinal cord by the ventral root. At the SP/MP synapse an excitatory transmitter is released that induces an impulse in MP which leads to contraction of protagonist muscle. However, excitation of I causes release of an inhibitory transmitter at the l/MA synapse which leads to relaxation of the antagonist muscle. Note that the basic reflex arc has been shown for simplicity but TeTx acts mainly on voluntary muscles.

2. A simplified version of the biochemical events occurring in synapses. Excitatory and inhibitory synapses, neurotransmitter release and action. Gly, glycine; R, receptors of neurotransmitters; X, hitherto uncharacterized (candidates include glutamate, dopamine, ATP, substance P, and somatostatin).

3. Sites of neurotoxin action. The predominant site of action of TeTx is the intermotor neuron synapse; the exocytotic machine is interfered with by the endopeptidase action of TeTx on VAMP. BoNT acts at the neuromuscular junction inhibiting the release of acetylcholine (Ach) by its proteolytic action on VAMP (types B, D and F) or SNAP (types A and E) or syntaxin (type C). (Reproduced with permission from Mims et at, 1995.)

depressed by prior binding of LF and this could explain the depression of edema produced by LF when added to EF and PA. The cell model does not explain or predict the increase in lethality resulting from addition of LF to EF and PA. However, it is now known that in high doses PA+LF is cytolytic to murine macrophages but that in very small sublytic doses it will stimulate expression of IL-1 and tumor necrosis factor (TNF). Protection of mice against LF is possible using passive transfer with anti-IL-1 or injection of IL-1 receptors, implying that, in mice at least, death could be due to the overstimulation of cytokines, particularly IL-1. LF is a putative Zn metalloprotease.

Other binary toxins

Clostridium botulinum C2 toxin (Figure 7) is not a neurotoxin but belongs to a family of cytotoxins. (C. perfringens iota toxin, C. spiroforme toxin, C. difficile ADP-ribosyltransferase) whose common features are that they are binary toxins and that they target cytoskeletal actin. Of these C. botulinum C2 is the best studied at present. Component C2I is the equivalent of the A subunit and C211, the B subunit. Both are produced in parallel although different strains produce different ratios. C2 is produced more during sporulation than in the vegetative phase of growth.

Figure 7 C. botulinum C2 toxin component 211 is activated by proteolysis and binds to the cell membrane followed by C2I. The latter is internalized and upsets the equilibrium between polymerization and depolymerization of actin. ADP-ribosylation of monomeric actin inhibits its polymerization and turns G-actin into a capping protein which binds to the fast-growing (barbed) ends of actin filaments. Capping of the barbed ends increases the critical concentration for actin polymerization. Since the slow-growing (pointed) ends of actin filaments are free, depolymerization of actin occurs at these ends. Released actin is substrate for the toxin and will be withdrawn from the treadmilling pool of actin by ADP-ribosylation, i.e. trapped. Both reactions will finally induce the breakdown of the microfilament network. The substrate specificity is high. The toxin will modify a specific arginine residue (177. present in all isoforms) in (3 and y nonmuscle actin and y smooth muscle actin but not in a isoforms of actin, which is surprising in view of the high degree of homology between the various isoforms of this protein. Neither component is toxic on its own but together the LD50 dose for a mouse is about 5-50 ng. The two components may be injected into different sites or by different routes but toxic effects always occur at the site of injection of C2II. (Reproduced with permission from Mims et al, 1995.)

Capping1

F-actin

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