Cross-talk between glucagon- and adenosine-mediated signalling systems in rat hepatocytes: effects on cyclic AMP-phosphodiesterase activity.
The effect of adenosine analogues on glucagon-stimulated cyclic AMP accumulation in rat hepatocytes was explored. N6-Cyclopentyladenosine (CPA), 5'-N-ethylcarboxamidoadenosine and N6-(R-phenylisopropyl)adenosine inhibited in a dose-dependent manner the cyclic AMP accumulation induced by glucagon. This effect seems to be mediated through A1 adenosine receptors. Pertussis toxin completely abolished the effect of CPA on glucagon-stimulated cyclic AMP accumulation in whole cells which suggested that a pertussis-toxin-sensitive G-protein was involved. On the other hand, this action of adenosine analogues on glucagon-induced cyclic AMP accumulation was reverted by the selective low-Km cyclic AMP-phosphodiesterase inhibitor Ro 20-1724. Analysis of cyclic AMP-phosphodiesterase activity in purified hepatocyte plasma membranes showed that glucagon in the presence of GTP inhibited basal PDE activity by 45% and that CPA reverted this inhibition in dose-dependent manner. In membranes derived from pertussis-toxin-treated rats, we observed no inhibition of cyclic AMP-phosphodiesterase activity by glucagon in the absence or presence of CPA. Our results indicate that in hepatocyte plasma membranes, stimulation of adenylate cyclase activity and inhibition of a low-Km cyclic AMP phosphodiesterase activity are co-ordinately regulated by glucagon, and that A1 adenosine receptors can inhibit glucagon-stimulated cyclic AMP accumulation by blocking glucagon's effect on phosphodiesterase activity.
Robles-Flores
M
M
Departamento de Bioenergética, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico, DF.
Allende
G
G
Piña
E
E
García-Sáinz
J A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D037361:Adenylate Cyclase Toxin; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D005934:Glucagon / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D037342:Pertussis Toxin; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; D010660:Phenylisopropyladenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C048599:N(6)-cyclopentyladenosine; D006160:Guanosine Triphosphate; D005934:Glucagon; D037342:Pertussis Toxin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000241:Adenosine