The light chain but not the heavy chain of botulinum A toxin inhibits exocytosis from permeabilized adrenal chromaffin cells

Stecher, Brigitte; Weller, Ulrich; Habermann, E.; Gratzl, Manfred; Ahnert‐Hilger, Gudrun

doi:10.1016/0014-5793(89)81129-9

Cited by 90 publications

(29 citation statements)

References 21 publications

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“…Ahnert-Hilger et al [6] have shown inhibition of catecholamine release from permeabilised adrenal chromaffin cells after treatment with the light chain of tetanus toxin alone or with the two-chain form in the presence of a reducing agent. Similar activities of the light chains of tetanus and of botulinum toxins (which are thought to have similar molecular mechanisms) have also been reported in other systems [7,8]. On the other hand, Poulain et al [9], working on Apiysia, reported that both the light and the heavy chains of botulinum toxin need to enter the cell before an effect is observed.…”

Section: Introduction Tetanus Toxin Is a Neurotoxin Secreted Bysupporting

confidence: 52%

The heavy chain of tetanus toxin can mediate the entry of cytotoxic gelonin into intact cells

1990

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An artificial conjugate of the heavy chain of tetanus toxin linked by a disulphide bond to the impermeant ribosome-inactivating protein gelonin is cytotoxic to intact HT29 cells by inhibiting intracellular protein synthesis. Neither toxin nor gelonin alone has any significant effect. This shows that the heavy chain has the ability to mediate internalization of a protein to which it is bound by a disulphide bond. Thus the normal role of the tetanus toxin heavy chain may be to allow entry of the light chain into a cell.

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Section: Introduction Tetanus Toxin Is a Neurotoxin Secreted Bysupporting

confidence: 52%

The heavy chain of tetanus toxin can mediate the entry of cytotoxic gelonin into intact cells

1990

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“…Again the situation resembles the one seen within chromaffin cells. Here the heavy chain does not change or rat her reduces the potency of the light chains of botulinum A toxin 21 or tetanus toxin. ' By contrast, in invertebrate neurons, such as those of the buccal ganglia of Aplysia, the roles of the chains are different.…”

Section: Discussionmentioning

confidence: 99%

Release of vasopressin from isolated permeabilized neurosecretory nerve terminals is blocked by the light chain of botulinum A toxin

et al. 1990

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Abstract-The intracellular action on exocytosis of botulinim A toxin and constituent chains was studied using permeabilized isolated nerve endings from the rat neural lobe. The release of the neuropeptide vasopressin was measured by radioimmunoassay. In the presence ofthe reducing agent dithiothreitol, the two-chain form of botulinum A toxin inhibited vasopressin release induced by 10 Jl M free calcium. Half maximal inhibition was obtained with 15 nM botulinum A toxin. In the absence of the heavy chain the light chain of the toxin strongly inhibited exocytosis with a half maximal effect of 2.5 nM. The inhibitory effects on secretion could be prevented by incubating the light chain with an immune serum against botulinum A toxin. The heavy chain of botulinum A toxin did not affect vasopressin release. However, it prevented the inhibitory effects of the light chain on stimulated exocytosis.It is concluded that botulinum A toxin inhibits the calcium-dependent step leading to exocytosis by interfering with a target present in the isolated and permeabilized nerve terminals. The functional domain of this neurotoxin, which is responsible for the inhibition of vasopressin release, is present in its light chain.Botulinum A toxin belongs to a family of cIosely reIated neurotoxins. The 150,000 mol. wt protein consists of a heavy chain (100,000 mol. wt) and a light chain (50,000 mol. wt) covalently linked by a disulfide bond. It inhibits neuro transmission at the peripheral cholinergic nerve endings by inhibiting neurotransmitter release. A three-step model is thought to produce the paralytic effects. It consists of (i) extracellular binding, (ii) internalization and (iii) intracellular poisoning (cf. Refs 12 and 19). The toxins' effects are restricted to the nervous tissue when given extracellularly. However, an extracellular application does not allow the differentiation of the intracellular processes involved in the final inhibition of transmitter release and the role played by the individual chains of the toxin.Recently, using cultured adrenal chromaffin cells permeabilized with streptolysin 0, it has been shown that intracellularly applied botulinum A toxin is more effective in the presence of a reducing agent. Indeed, the light chain of botulinum A toxin alone inhibited Ca 2 + -stimulated catecholamine release. 5 ,20,21 In contrast, both the heavy and the light chain must be tPresent address:

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“…Catecholamine release from adrenal chromaffin cells, vasopressin release from neurohypophysial terminals and insulin release from pancreatic 13 cells is inhibited by botulinum neurotoxin A [14][15][16][17][18]. However, the variable cleavage of SNAP-25 in pancreatic [3 cells, the incomplete inhibition of vasopressin and catecholamine release and the preferential attack of ATP-dependent priming by botulinum neurotoxin A suggested that this toxin may have molecular targets of different sensitivities [14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Adrenal chromaffin cells contain functionally different SNAP‐25 monomers and SNAP‐25/syntaxin heterodimers

Höhne-Zell¹,

Gratzl²

1996

FEBS Letters

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The light chain but not the heavy chain of botulinum A toxin inhibits exocytosis from permeabilized adrenal chromaffin cells

Cited by 90 publications

References 21 publications

The heavy chain of tetanus toxin can mediate the entry of cytotoxic gelonin into intact cells

The heavy chain of tetanus toxin can mediate the entry of cytotoxic gelonin into intact cells

Release of vasopressin from isolated permeabilized neurosecretory nerve terminals is blocked by the light chain of botulinum A toxin

Adrenal chromaffin cells contain functionally different SNAP‐25 monomers and SNAP‐25/syntaxin heterodimers

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