Nagy L E, Diamond I, Gordon A S
Ernest Gallo Clinic and Research Center, University of California, San Francisco 94110.
Mol Pharmacol. 1991 Nov;40(5):812-7.
Ethanol inhibits adenosine uptake, thereby increasing the concentration of extracellular adenosine. Elevation of extracellular adenosine increases intracellular cAMP concentration via activation of adenosine A2 receptors. Extracellular adenosine is also required for the subsequent development of ethanol-induced heterologous desensitization. Here we report that activation of cAMP-dependent protein kinase is necessary for inhibition of adenosine uptake by ethanol and for the consequent accumulation of extracellular adenosine. Ethanol does not inhibit adenosine uptake in mutants of the S49 cell line that lack receptor-stimulated cAMP production (unc cells) or cAMP-dependent protein kinase activity (kin- cells). Forskolin, which bypasses the receptor-coupling defect in unc cells to increase cAMP levels, restores inhibition of adenosine uptake by ethanol. In contrast, in kin- cells forskolin did not restore inhibition of adenosine uptake by ethanol, despite similar increases in cAMP levels. Taken together, these results suggest that cAMP-dependent protein kinase phosphorylates a component of the nucleoside transporter, thereby regulating the sensitivity of adenosine transport to ethanol.
乙醇抑制腺苷摄取，从而增加细胞外腺苷的浓度。细胞外腺苷浓度的升高通过激活腺苷A2受体增加细胞内cAMP浓度。细胞外腺苷对于乙醇诱导的异源脱敏的后续发展也是必需的。在此我们报告，cAMP依赖性蛋白激酶的激活对于乙醇抑制腺苷摄取以及随后细胞外腺苷的积累是必要的。在缺乏受体刺激的cAMP产生的S49细胞系突变体（unc细胞）或cAMP依赖性蛋白激酶活性（kin-细胞）中，乙醇不抑制腺苷摄取。福斯可林绕过unc细胞中的受体偶联缺陷以增加cAMP水平，可恢复乙醇对腺苷摄取的抑制作用。相反，在kin-细胞中，尽管cAMP水平有类似升高，但福斯可林并未恢复乙醇对腺苷摄取的抑制作用。综上所述，这些结果表明，cAMP依赖性蛋白激酶使核苷转运体的一个组分磷酸化，从而调节腺苷转运对乙醇的敏感性。
