摘要：

We have obtained evidence that receptor-stimulated adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] is regulated physiologically in both embryonic and mature neurons. In a series of experiments using cultured retina cells from chicken embryos, we found that dopamine-sensitive adenylate cyclase activity spontaneously desensitized as cultures differentiated. The cellular response to dopamine reached a maximum after 5 days in culture and then decreased to 40% during the next 5 days. This spontaneous desensitization appeared to be caused by functional dopaminergic transmission because it could be blocked by the dopamine antagonist haloperidol. The ability of added dopamine at 100 μ M to cause near-complete desensitization is consistent with this conclusion. Pharmacologically induced desensitization required 31 hr for maximal effect and was half-maximal at 1-10 μ M dopamine. Analogous desensitization of the adenosine-dependent adenylate cyclase system also was noted. When dopamine was removed from the medium of chronically treated cultures, cells resensitized to subsequent stimulation at a very slow rate. Resensitization likely depended on replacement of dopamine receptors because chronic dopamine treatment caused the disappearance of binding sites for the ligand [3H]spiroperidol. In a second series of experiments, using hatched animals, we found that similar regulation of dopamine receptor binding sites and activity could be elicited by manipulation of environmental light, a treatment thought to influence dopaminergic transmission. Retinas from animals in constant light had less specific [3H]spiroperidol binding (35 fmol/mg of protein) than did retinas from animals in constant darkness (66 fmol/mg of protein) and made less cAMP in response to added dopamine. Our results indicate that regulation of the dopamine receptor system begins early in development and continues to function in mature synapses.

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