title: Stimulation of glucose production from glycogen by glucagon, noradrenaline and non-degradable adenosine analogues is counteracted by adenosine and ATP in cultured rat hepatocytes.
abstract: The glycogenolytic potency of adenosine and ATP was studied in adult rat hepatocytes and compared with the action of glucagon and noradrenaline. In cells cultured for 48 h, adenosine and ATP as well as their analogues 2-chloroadenosine, phenylisopropyladenosine, N-ethylcarboxamidoadenosine and beta-gamma-methylene-substituted ATP (p[CH2]ppA) increased glycogen phosphorylase alpha to levels indistinguishable from those obtained by the addition of glucagon or noradrenaline. The P1 receptor antagonist 8-phenyltheophylline abolished the activation of phosphorylase by adenosine and by p[CH2]ppA, but not that by ATP. Protein kinase A was activated by p[CH2]ppA and ATP via their breakdown to adenosine. [14C]Glucose production from glycogen was stimulated only 3-fold by ATP and adenosine, compared with a 7-fold increase produced by the hormones. Stimulation of glucose production by glucagon or noradrenaline was almost completely abolished by ATP or adenosine, with half-maximal effects at around 10 microM. The non-degradable adenosine analogues were equipotent with glucagon with respect to stimulation of glucose production, and their action was also inhibited by adenosine. ATP and p[CH2]ppA, which were both degraded to adenosine, showed comparable metabolic effects, whereas the alpha, beta-methylene analogue was without biological action and also was not degraded to adenosine. In the presence of the adenosine transport inhibitor nitrobenzyl thioinosine (NBTI), adenosine exerted an increased glycogenolytic potency, reaching 80% of the maximal stimulation obtained by glucagon. The glucagon-antagonistic effect of adenosine could be completely abolished by NBTI, but was not affected by phenyltheophylline. It is concluded that, in the hepatocyte culture system, adenosine and ATP decrease the catalytic efficiency of phosphorylase alpha through signals arising from their uptake into the cell.
authors.affiliation: Institut für Biochemie, Georg-August Universität, Göttingen, Federal Republic of Germany.
authors.forename: E
authors.initials: E
authors.lastname: Oetjen
authors.forename: C
authors.initials: C
authors.lastname: Schweickhardt
authors.forename: K
authors.initials: K
authors.lastname: Unthan-Fechner
authors.forename: I
authors.initials: I
authors.lastname: Probst
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000096:biosynthesis*; D006003:Glycogen / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; D013868:Thioinosine; D000255:Adenosine Triphosphate; D006003:Glycogen; D005934:Glucagon; D000242:Cyclic AMP; C001789:4-nitrobenzylthioinosine; D005947:Glucose; D000241:Adenosine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D009638:Norepinephrine