G proteins Gαi1/3 are critical targets for Bordetella pertussis toxin-induced vasoactive amine sensitization.
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 approach, we identified the HA H1 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 controlled 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 Gαi/o G-protein subunits, we demonstrate that Gαi1 and Gαi3 are the critical in vivo targets of ADP-ribosylation underlying VAAS elicited by PTX exposure.
Department of Medicine-Infectious Diseases, University of Vermont College of Medicine, Burlington, Vermont, USA.
Sean A
SA
Diehl
Benjamin
B
McElvany
Rajkumar
R
Noubade
Nathan
N
Seeberger
Brock
B
Harding
Karen
K
Spach
Cory
C
Teuscher
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000588:Amines / Q000378:metabolism*; D000818:Animals; D001886:Bordetella pertussis / Q000472:pathogenicity*; D002317:Cardiovascular Agents / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D037342:Pertussis Toxin / Q000378:metabolism*
D000588:Amines; D002317:Cardiovascular Agents; C579276:Gnai1 protein, mouse; D000246:Adenosine Diphosphate Ribose; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse