Different modulation of inhibitory and stimulatory pathways mediated by adenosine after chronic in vivo agonist exposure.
After 6 days of in vivo treatment with two selective adenosine receptor agonists, 5'-N-ethylcarboxamido adenosine (NECA) and R-N6-phenylisopropiladenosine (R-PIA), we investigated their effects on adenosine receptors/adenylyl cyclase system in synaptic plasma membranes isolated from rat brain. NECA treatment caused a significant loss of NECA-stimulated adenylyl cyclase activity, suggesting a desensitization of the adenosine A2 receptors-mediated pathway. No significant differences in total adenosine A2 receptors were observed, but Gs protein levels were decreased, suggesting Gs down-regulation as a mechanism for desensitization. On the other hand, NECA treatment caused a significant decrease in high-affinity adenosine A1 receptors population; however, no changes in CHA-inhibited adenylyl cyclase activity or Gi protein level were observed. Finally, when we studied the effects of R-PIA, a selective adenosine A1 receptor agonist, on stimulatory pathway of adenosine, low-affinity adenosine A2 binding sites were decreased without affecting the functionality of the pathway. These results show that adenosine A1 and A2 receptors are modulated in a different way after chronic agonist exposure and suggest the existence of cross-talk mechanisms between both stimulatory an inhibitory pathways mediated by adenosine.
Ruiz
María Angeles
MA
Area de Bioquímica, Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Químicas, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10. 13071 Ciudad Real, Spain.
Albasanz
José Luis
JL
León
David
D
Ros
Manuel
M
Andrés
Antonio
A
Martín
Mairena
M
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000008:administration & dosage; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002462:Cell Membrane / Q000201:enzymology; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013570:Synaptic Membranes / Q000201:enzymology*
D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha; C047235:N-(1-methyl-2-phenylethyl)adenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D000241:Adenosine