Dual mechanisms involved in development of diverse biological activities of islet-activating protein, pertussis toxin, as revealed by chemical modification of lysine residues in the toxin molecule

Pertussis toxin stimulates delayed‐onset, Ca2+‐dependent catecholamine release and the ADP‐ribosylation of a 40 kDa protein in bovine adrenal chromaffin cells

“…However, it is difficult to reconcile the finding that pertussis toxin induces catecholamine release in the absence of any exogenous receptor agonist with the current understanding of the mechanism of action of the toxin, which is supposed to involve the uncoupling of a receptor from a G-protein through the ADPribosylation of the latter. It is possible that pertussis toxin-induced catecholamine release is analogous to the pertussis toxin-induced lipolysis in rat adipocytes [21]. Adenosine released from the adipocytes inhibits adenylyl cyclase and lipolysis through Gi, but pertussis toxin blocks this inhibition with the result that the toxin apparently induces spontaneous glycerol release with kinetics very similar to the toxin-induced catecholamine release.…”

Identification of a region in the S1 subunit of pertussis toxin that is required for enzymatic activity and that contributes to the formation of a neutralizing antigenic determinant.

“…PIX appears to exert many of its biological effects in eukaryotic cells through the ADP-ribosylation of membrane-bound guanine nucleotide-binding regulatory components (N, or Gi) of the adenylate cyclase complex (7,8). The enzymatic activity of PTX is associated with the S1 subunit.…”

Reversal of the CD4+/CD8+T-Cell Ratio in Lymph Node Cells upon In Vitro Mitogenic Stimulation by Highly Purified, Water-Soluble S3-S4 Dimer of Pertussis Toxin

“…It is highly relevant to point out the circumstantial evidence suggesting that the S3-S4 dimer is most likely implicated in the mitogenicity of the B oligomer, whereas the S2-S4 dimer may only play a more minor role in this function. Studies have used methylated PT to analyze the involvement of the various PT components in the biological activity of PT (20,21). Chemical modification of PT by methylation of lysine residues does not significantly interfere with the A protomer-transporting activity of the B oligomer but results in loss of the mitogenic activity of PT (21).…”

“…A number of the biological activities of PT, such as lymphocytosis and adjuvant activity, implicate the enzymatic activity of PT in its toxicity and can be abrogated by inactivation of the S1 subunit (1, 5, 13). In contrast, PT-associated T-cell mitogenicity is mediated by the B oligomer (9, 31, 36) and appears to be independent of the enzymatic activity of the toxin, as inactivation of the S1 subunit by mutation has no effect on the mitogenic activity of PT (13,36), while alterations in the B oligomer can totally abrogate the mitogenic activity of PT (15,16,[20][21][22]. In addition, the B oligomer devoid of S1 induces T-cell proliferation to the same extent as PT (22,29,31,32,36).…”

“…However, there is evidence of a difference between the binding specificities of the two dimers (26,37), which may account for observations leading to the suggestion that the B oligomer must bind to the cell surface to permit translocation of the A protomer into the cell in a manner different from its binding leading to T-cell mitogenicity, since these two types of binding displayed different susceptibilities to chemical modification of the molecule (22; see Discussion). Experiments with hybrid PTs composed of various combinations of chemically modified dimers indicate a differential role of the two dimers in T-cell stimulation and suggest that the S3-S4 dimer is more relevant to the binding of the B oligomer which results in T-cell stimulation than to the binding which results in translocation of the S1 subunit (20)(21)(22). A mitogenic effect for the S3-S4 dimer as an isolated dimeric molecule was not demonstrated.…”