ACTIVATION OF ADENYLATE-CYCLASE BY CHOLERAGEN

Choleragen (cholera toxin) is an enterotoxin of Vibrio cholerae that is responsible for the watery diarrhea characteristic of clinical cholera. The toxin is an oligomeric protein of ~84,000 daltons composed of three dissimilar peptides, A1, A2 and B. A1 (23,500) is linked through a single disulfide bond to A2, a peptide of 5500 daltons. Five B subunits (11,600 daltons) are present in the oligomer. Choleragen is believed to exert its effect on cells through activation of adenylate cyclase. The initial event appears to be the binding of the B subunits of the toxin to ganglioside G(M1) on the cell surface. Although the mechanism by which choleragen gains access to adenylate cyclase or its regulatory component is unclear, lateral mobility of the toxin on the cell surface or within the membrane may be necessary. Multivalent binding of the B subunits to the cell surface, followed by patching and/or capping of the toxin may facilitate entry. E. coli heat-labile enterotoxin is similar in many ways to choleragen. The toxin utilizes a ganglioside, probably G(M1), as a cell surface recpetor and requires NAD for in vitro activation of adenylate cyclase. In addition, it catalyzes the hydrolysis of NAD, the ADP-ribosylation of proteins, and the stereospecific β-NAD-dependent ADP-ribosylation of arginine to yield α-ADP-ribose-L-arginine. Recently, an enzyme has been isolated from avian erythrocytes that also possesses NAD glycohydrolase and ADP-ribosyltransferase activities. It will activate brain adenylate cyclase in the presence of NAD. Although a physiological role for this enzyme remains to be established, its presence is consistent with the possibility that vertebrate cells may use mechanisms for physiological activation of adenylate cyclase that are similar to those through which the choleragen and Escherichia coli toxins procude disease.