A 28-year-old aid worker presents to a field clinic with severe, voluminous watery diarrhea and leg cramps. The responsible pathogen produces an AB-type exotoxin that causes profound fluid loss. Arrange the following steps of this toxin's cellular mechanism of action in the correct pathophysiological sequence, from initial interaction with the host cell to the ultimate physiologic effect.
- 1Binding of the toxin's B subunit to the GM1 ganglioside receptor on the apical enterocyte membrane.
- 2Endocytosis of the toxin complex and transport, allowing the active A subunit to enter the host cytosol.
- 3ADP-ribosylation and permanent activation of the stimulatory G-protein alpha subunit (Gs).
- 4Constitutive activation of adenylate cyclase with subsequent intracellular accumulation of cyclic AMP (cAMP).
- 5Activation of protein kinase A (PKA) leading to prolonged opening of the CFTR channel and luminal fluid efflux.
Cevap
The correct sequence of Vibrio cholerae toxin action is: 1) Binding to GM1 ganglioside, 2) Internalization of the A subunit, 3) ADP-ribosylation of the Gs protein, 4) Activation of adenylate cyclase causing increased cAMP, and 5) Activation of PKA leading to CFTR channel opening and secretory diarrhea.
The pathogenesis of Vibrio cholerae relies on its AB exotoxin. The B (binding) subunit attaches to GM1 ganglioside receptors on intestinal epithelial cells. Once endocytosed, the active A subunit escapes into the cytosol where it catalyzes the ADP-ribosylation of the Gs alpha subunit. This modification locks Gs in an active state, causing continuous stimulation of adenylate cyclase and a massive increase in intracellular cAMP. Elevated cAMP activates protein kinase A, which phosphorylates and opens the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) channel. The resulting massive efflux of chloride ions into the intestinal lumen is followed by sodium and water, producing the characteristic severe secretory diarrhea.
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Anahtar Kavram
Cholera toxin mechanism of action