title: Pertussis toxin inhibition of alpha 1-adrenergic or vasopressin-induced Ca2+ fluxes in rat liver. Selective inhibition of the alpha 1-adrenergic receptor-coupled metabolic activation.
abstract: Pretreatment with pertussis toxin produced a impairment of the response to the alpha-adrenergic agonist phenylephrine in perfused isolated rat livers. The sustained phases of phenylephrine-induced increases in respiration, glucose mobilization, gluconeogenesis, vascular resistance, and efflux of H+ and Ca2+ were inhibited to variable degrees in livers from pertussis toxin-treated animals. The susceptibility of such a diversity of receptor-mediated effects suggests that a common, most likely early step(s) of the alpha 1-receptor-coupled signaling pathway may be regulated by a pertussis toxin-sensitive Gi protein(s) that appears to be involved in the control of the rate of these processes. The most significant effect of pertussis toxin has been to almost entirely prevent the phenylephrine-induced sustained release of Ca2+. Pertussis toxin also inhibited the vasopressin-mediated influx of Ca2+. These findings indicate that G proteins associated with receptor-operated calcium channels are a site of interaction of pertussis toxin. The following observations support the conclusion that pertussis toxin per se does not perturb the hepatic metabolism. Its effects are specifically linked to functional responses mediated by alpha 1-type adrenergic receptors: 1) polypeptide receptor-mediated metabolic effects, as those induced by vasopressin, were not affected by pertussis toxin; 2) non-receptor-mediated effects, such as fatty acid-induced stimulation of respiration and gluconeogenesis, were not impaired by pertussis toxin; and 3) neither the hepatic responses to alpha 2-(clonidine) nor to beta-(isoproterenol) adrenergic receptor agonists were altered in livers from pertussis toxin-treated rats. The differential effects of pertussis toxin in the metabolic actions of phenylephrine and vasopressin, in spite of apparently similar effects in perturbing their actions on Ca2+ fluxes, suggest that pertussis toxin-sensitive alpha 1-receptor-associated G protein(s) other than those controlling Ca2+ channels, were also specifically affected in the alpha 1-agonist-signaling pathway. The finding that increasing concentrations of phenylephrine were capable of overcoming these pertussis toxin actions indicates that alpha 1-adrenoreceptors' ligand affinity is controlled by Gi proteins.
authors.affiliation: Endocrine Physiology Unit, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Butta
authors.forename: E
authors.initials: E
authors.lastname: Urcelay
authors.forename: C
authors.initials: C
authors.lastname: González-Manchón
authors.forename: R
authors.initials: R
authors.lastname: Parrilla
authors.forename: M S
authors.initials: MS
authors.lastname: Ayuso
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane; D019204:GTP-Binding Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D037342:Pertussis Toxin; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014667:Vasopressins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D014662:Vasoconstrictor Agents; D010566:Virulence Factors, Bordetella; D014667:Vasopressins; D010656:Phenylephrine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium