Mechanism of enhanced sensitivity to bradykinin in pertussis toxin-treated fibroblasts: toxin increases bradykinin-stimulated prostaglandin formation.
Exposure of animals to pertussis toxin results in increased sensitivity to agents such as bradykinin. To elucidate the molecular mechanisms underlying the effects of toxin, bradykinin responsiveness was examined in control and intoxicated human fibroblasts. Exposure of fibroblasts to toxin resulted in a loss of inhibitory agonist action on adenylate cyclase, elevation of basal cAMP, and ADP-ribosylation of a 41-kDa protein, which was identified as Gi alpha, a component of adenylate cyclase, by its pattern of immuno-cross-reactivity with a family of antibodies to guanyl nucleotide-binding proteins, which are pertussis toxin substrates, and by the presence of an mRNA species with characteristics of a form of Gi alpha. Bradykinin increased prostaglandin accumulation to a greater extent in toxin-treated than in control fibroblasts. Agents such as cholera toxin, which elevated cAMP, also increased bradykinin-induced prostaglandin production. These data are consistent with the hypothesis that the enhanced sensitivity to bradykinin after pertussis toxin treatment results from modification of Gi alpha and increased cAMP, leading to enhanced formation of prostaglandins in response to bradykinin.
Moss
J
J
Laboratory of Cellular Metabolism, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
Hom
B E
BE
Hewlett
E L
EL
Tsai
S C
SC
Adamik
R
R
Halpern
J L
JL
Price
S R
SR
Manganiello
V C
VC
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D005347:Fibroblasts / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D037342:Pertussis Toxin; D011453:Prostaglandins / Q000096:biosynthesis*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D011453:Prostaglandins; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001920:Bradykinin