title: Glycogen phosphorylase activation by two different alpha 1-adrenergic receptor subtypes: methoxamine selectively stimulates a putative alpha 1-adrenergic receptor subtype (alpha 1a) that couples with Ca2+ influx.
abstract: We compared the effects of methoxamine on alpha 1-adrenergic receptor-mediated phosphorylase activation in rat hepatocytes and rabbit aorta. Although methoxamine is a potent agonist in activating phosphorylase of rabbit aorta, it had little effect in rat hepatocytes. Using the phenoxybenzamine inactivation method, we found that the quantitative relationship between 125I-BE2254 (125I-BE) binding capacity and maximal norepinephrine-stimulated phosphorylase activation was nonlinear in rabbit aorta, whereas it was linear in rat hepatocytes. The potency of methoxamine in inhibiting specific 125I-BE binding is significantly (p less than 0.05) higher in rabbit aorta (Kd, 96.4 +/- 7.7 microM), compared with rat hepatocytes (Kd, 283 +/- 16 microM). However, these quantitative differences could not fully explain the blunted [Ca2+]c and phosphorylase responses to methoxamine in rat hepatocytes. Treatment with chlorethylclonidine dose dependently suppressed 125I-BE binding sites and norepinephrine-induced phosphorylase activation in rat hepatocytes, whereas in rabbit aorta it resulted in only a 31% decrease in 125I-BE binding sites, with little effect on phosphorylase activation. Furthermore, alpha 1-adrenergic receptor-mediated cellular events of phosphatidylinositol (PI) hydrolysis and phosphorylase activation were unaffected by the removal of extracellular Ca2+ in rat hepatocytes, whereas both responses were markedly attenuated in rabbit aorta. The results indicate that two different alpha 1-adrenergic receptor subtypes activate glycogen phosphorylase, through different mechanisms for increasing [Ca2+]c in the two systems. In rat hepatocytes, alpha 1 receptors are closely linked to PI hydrolysis and Ca2+ release from intracellular stores and cause phosphorylase activation. In rabbit aorta, on the other hand, activation of alpha 1 receptors increases [Ca2+]c by Ca2+ influx from the extracellular fluid as well as by Ca2+ release, and both PI hydrolysis and phosphorylase activation are caused mainly by the Ca2+ entry. Methoxamine interacts with both chlorethylclonidine-sensitive and -insensitive alpha 1 receptor subtypes but selectively stimulates the alpha 1 receptor subtype that closely couples with the Ca2+ influx.
authors.affiliation: Department of Pharmacology, Yamanashi Medical College, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: A
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: E
authors.initials: E
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D010627:Phenethylamines / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D006005:Phosphorylases / Q000032:analysis*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000187:drug effects*; D044024:Tetralones
chemical_list: D007295:Inositol Phosphates; D010627:Phenethylamines; D011942:Receptors, Adrenergic, alpha; D044024:Tetralones; D010656:Phenylephrine; C051731:chlorethylclonidine; C010652:BE 2254; D006005:Phosphorylases; D008729:Methoxamine; D003000:Clonidine; D002118:Calcium; D004837:Epinephrine