Coupling of adenosine receptors to adenylate cyclase in postischemic rat brain.
The potential usefulness of adenosine receptor stimulation in the therapy for ischemic brain disease is dependent upon retention of adenosine receptors and their transduction mechanisms after ischemia. The receptors most clearly associated with adenosine-dependent cerebral inhibition are the A1-type (A1-AR), which work via a Gi protein to inhibit adenylate cyclase. In brain membranes from rats recovering at various times after 15 min of complete cardiac arrest-induced ischemia, the levels of A1-AR decreased temporarily to 60% of the control values. However, agonist affinities for A1-AR, as well as guanine nucleotide-sensitive high-affinity binding, remain unchanged. The significant decrease of agonist affinities to A1-AR produced by calcium depletion in control membranes was markedly attenuated after ischemia. Moreover, the A1-AR agonist-induced inhibition of cAMP production parallels the decrease in these receptor numbers. It was blocked in the postischemic membranes but reverts to control levels upon extending the recovery period to one week after the insult. It is concluded that in addition to the lowering of the number of A1-AR binding sites, the coupling of A1 receptor activation to adenylate cyclase response is inhibited after ischemia, but not at the level of receptor-Gi protein interaction.
Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, Warsaw.
K
K
Domanska-Janik
S
S
Pyłowa
T
T
Zalewska
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D019830:Adenosine-5'-(N-ethylcarboxamide); D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D001667:Binding, Competitive; D002545:Brain Ischemia / Q000209:etiology / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D015536:Down-Regulation; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006323:Heart Arrest / Q000150:complications; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D011983:Receptors, Purinergic / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D000067956:Adenylyl Cyclase Inhibitors; D011983:Receptors, Purinergic; D005576:Colforsin; D019830:Adenosine-5'-(N-ethylcarboxamide); D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004533:Egtazic Acid; D006160:Guanosine Triphosphate; D004492:Edetic Acid; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000241:Adenosine; D002118:Calcium