Blanchet Christophe, Lüscher Christian
Pharmacology, Department of Physiology, and Neurology, University of Geneva, CH 1211 Geneva, Switzerland.
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4674-9. doi: 10.1073/pnas.072075399. Epub 2002 Mar 26.
Many G protein-coupled receptor-mediated responses desensitize within minutes. Sustained stimulation of mu-opioid receptors (MORs), which primarily signal through G(i/o) proteins, leads to activation and subsequent desensitization of G protein-coupled inwardly rectifying potassium (GIRK) currents. We observed that in neurons of the locus coeruleus, which express among the highest levels of MORs in the brain, the degree of desensitization depended on the intensity of receptor stimulation, indicating that the process is initiated at the receptor. Interestingly, while GIRK-mediated postsynaptic inhibition substantially desensitized within 15 min, presynaptic inhibition of afferent transmission, which involves other effector systems, remained constant, suggesting that the postsynaptic desensitization we observed is expressed at the effector. We show that desensitized GIRK currents can gradually be reactivated by additional G protein signals of increasing intensity and present evidence that desensitization is a G protein-mediated process. Finally, desensitization of MOR-induced GIRK currents had heterologous effects on responses mediated by other G protein-coupled receptors converging onto the same population of GIRK channels. Taken together, our results provide evidence for a form of desensitization mediated by a slowly developing G protein-dependent pathway, initiated at the MORs and leading to competitive inhibition of GIRK channel activation. This implies that MORs exert a bidirectional action on GIRK channels.
许多G蛋白偶联受体介导的反应在数分钟内就会脱敏。对主要通过G(i/o)蛋白发出信号的μ-阿片受体（MOR）的持续刺激，会导致G蛋白偶联内向整流钾通道（GIRK）电流的激活及随后的脱敏。我们观察到，在蓝斑核神经元中，其在大脑中表达的MOR水平最高，脱敏程度取决于受体刺激的强度，这表明该过程始于受体。有趣的是，虽然GIRK介导的突触后抑制在15分钟内基本脱敏，但涉及其他效应系统的传入传递的突触前抑制保持不变，这表明我们观察到的突触后脱敏是在效应器水平表达的。我们表明，脱敏的GIRK电流可以被强度不断增加的额外G蛋白信号逐渐重新激活，并提供证据表明脱敏是一个G蛋白介导的过程。最后，MOR诱导的GIRK电流脱敏对由汇聚到同一群GIRK通道上的其他G蛋白偶联受体介导的反应具有异源效应。综上所述，我们的结果为一种由缓慢发展的G蛋白依赖性途径介导的脱敏形式提供了证据，该途径始于MOR并导致对GIRK通道激活的竞争性抑制。这意味着MOR对GIRK通道发挥双向作用。
