Nagy L E, Diamond I, Collier K, Lopez L, Ullman B, Gordon A S
Ernest Gallo Clinic, San Francisco, California.
Mol Pharmacol. 1989 Nov;36(5):744-8.
Recent evidence suggests that ethanol initially causes an increase in receptor-dependent cAMP levels, followed by heterologous desensitization of receptors coupled to GS after chronic exposure. Here we investigated the role of adenosine in mediating these responses. We found that ethanol caused accumulation of extracellular adenosine in NG108-15 and S49 lymphoma cells. This adenosine activated adenosine receptors to increase intracellular cAMP levels. The addition of adenosine deaminase, to degrade accumulated extracellular adenosine, or isobutyl-methylxanthine, an adenosine receptor antagonist, completely blocked ethanol-induced increases in cAMP levels in NG108-15 cells. Chronic exposure of NG108-15 and S49 wild type cells to ethanol resulted in heterologous desensitization of adenosine receptor- and prostaglandin E1 receptor-dependent cAMP signal transduction. Coincubation of NG108-15 and S49 wild type cells with adenosine deaminase and ethanol for 48 hr prevented heterologous desensitization. Moreover, mutant S49 cells, which are unable to transport adenosine, did not accumulate extracellular adenosine after incubation with ethanol and did not develop ethanol-induced heterologous desensitization. Our results suggest that adenosine is an important mediator of both the acute and chronic effects of ethanol on cAMP signal transduction.
最近的证据表明，乙醇最初会导致受体依赖性cAMP水平升高，长期暴露后，与GS偶联的受体会发生异源脱敏。在此，我们研究了腺苷在介导这些反应中的作用。我们发现，乙醇会导致NG108-15和S49淋巴瘤细胞中细胞外腺苷的积累。这种腺苷激活腺苷受体以增加细胞内cAMP水平。添加腺苷脱氨酶以降解积累的细胞外腺苷，或添加腺苷受体拮抗剂异丁基甲基黄嘌呤，可完全阻断乙醇诱导的NG108-15细胞中cAMP水平的升高。将NG108-15和S49野生型细胞长期暴露于乙醇会导致腺苷受体和前列腺素E1受体依赖性cAMP信号转导的异源脱敏。将NG108-15和S49野生型细胞与腺苷脱氨酶和乙醇共同孵育48小时可防止异源脱敏。此外，无法转运腺苷的突变型S49细胞在与乙醇孵育后不会积累细胞外腺苷，也不会出现乙醇诱导的异源脱敏。我们的结果表明，腺苷是乙醇对cAMP信号转导的急性和慢性影响的重要介质。
