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.
Islet-activating protein (IAP), pertussis toxin, is an oligomeric protein composed of an A-protomer and a B-oligomer. There seem to be at least two molecular mechanisms by which IAP exerts its various effects in vivo and in vitro. On the one hand, some of the effects were not significantly affected by acetamidination of the epsilon-amino groups of the lysine residues in the molecule. These include the activities in vitro (1) catalyzing ADP-ribosylation of one of the membrane proteins directly, (2) enhancing membrane adenylate cyclase activity in C6 cells, (3) reversing receptor-mediated inhibition of insulin or glycerol release from pancreatic islets or adipocytes, respectively, and the activities in vivo (4) inhibiting epinephrine-induced hyperglycemia, (5) potentiating glucose-induced hyperinsulinemia, (6) reducing hypertension and increasing the heart rate in genetically hypertensive rats. These activities are concluded to develop as a result of ADP-ribosylation catalyzed by the A-protomer which is rendered accessible to its intramembrane substrate thanks to the associated B-oligomer moiety. Thus, neither the enzymic activity of the A-protomer nor the transporting activity of the B-oligomer needs free amino groups of the lysine residues in the IAP molecule. On the other hand, additional effects of IAP, such as (1) mitogenic, (2) lymphocytosis-promoting, (3) histamine-sensitizing, (4) adjuvant and (5) vascular permeability increasing, were markedly suppressed by acetamidination of the intrapeptide lysine residues. The free epsilon-amino group of lysine would play an indispensable role in the firm (or divalent) attachment of the B-oligomer of IAP to the cell surface that is responsible for development of these activities.
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001427:Bacterial Toxins / Q000302:isolation & purification / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006632:Histamine / Q000633:toxicity; D007096:Imidoesters; D007202:Indicators and Reagents; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008218:Lymphocytosis / Q000139:chemically induced; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens; D037342:Pertussis Toxin; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D001427:Bacterial Toxins; D007096:Imidoesters; D007202:Indicators and Reagents; D007328:Insulin; D008934:Mitogens; D010566:Virulence Factors, Bordetella; C014539:ethyl acetimidate; D000246:Adenosine Diphosphate Ribose; D006632:Histamine; D037342:Pertussis Toxin