G Proteins Gi1/3 Are Critical Targets for Bordetella pertussis Toxin-

Pertussis toxin (PTX) is an AB5-type exotoxin produced by the bacterium Bordetella pertussis, the causative agent of whooping cough. In vivo intoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic ap-proach, we identified the HAH1 receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility to B. pertussis PTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1 hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately con-trolled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gi/o G-protein subunits, we demonstrate that Gi1 and Gi3 are the critical in vivo targets of ADP-ribosylation underlying VAAS elicited by PTX exposure. Infection with the bacterium Bordetella pertussis can lead towhooping cough, usually typified by paroxysomal coughing and, in severe cases, oropharyngeal tissue swelling, hypertension, pneumothorax, and long-lasting aftereffects (1). The principal ac-tive agent in B. pertussis, pertussis toxin (PTX), is an AB5-typ