Sequence of events in the activation of adenylate cyclase by cholera toxin.
The toxin of Vibrio Cholera causes fluid secretion from the small intestine by stimulation of adenylate cyclase and elevation of intracellular cyclic AMP concentrations. The toxin is a protein composed of subunits responsible for binding to cell membranes and a subunit responsible for the activation of adenylate cyclase. The binding subunits (B) are non-covalently bonded to the active subunit (A). The latter is composed of two polypeptides A1 and A2 linked by a disulphide bridge. Exposure of the intestine to toxin results in rapid binding to the brush border membrane. Thence follows a gradual increase in adenylate cyclase activity, and stimulation of electrolyte and fluid secretion. Enzyme localization studies show that the brush border does not contain adenylate cyclase. Thus the stimulation of adenylate cyclase by toxin which interacts with the brush border must be indirect. From recent studies it seems that an activator of adenylate cyclase can be found in cytosol from toxin-treated cells. Incubation of toxin with cytosol or dithiothreitol results similarly in the formation of an activator. Preincubation of toxin with cytosol results in more rapid activation of adenylate cyclase in liver cell membranes than direct addition of cytosol and toxin. Preincubation of cholera toxin for activation, by cytosol, is presumed to be due to the splitting of the disulphide band between the A1 and A2 components of the active subunit. The stimulatory ability resides in A1 and both A1 and NAD are required for the activation of adenylate cyclase. The toxin-stimulated adenylate cyclase has similar characteristics to the enzyme stimulated by non-hydrolysable analogs of GTP such as guanylylimidodiphosphate (GppNHp). Stimulation by either cholera or GppNHp is irreversible, the responses to catecholamines are enhanced and the enzyme can be solubilized in the activated state.
D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D000818:Animals; D002463:Cell Membrane Permeability; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D006868:Hydrolysis; D007421:Intestine, Small / Q000201:enzymology; D051381:Rats; D014118:Toxins, Biological / Q000494:pharmacology*; D014734:Vibrio cholerae
D014118:Toxins, Biological; D000262:Adenylyl Cyclases