Department of Neurobiology, Hebrew University, Jerusalem, Israel.
PLoS One. 2010 Jan 22;5(1):e8752. doi: 10.1371/journal.pone.0008752.
Depolarization induced charge movement associated currents, analogous to gating currents in channels, were recently demonstrated in G-protein coupled receptors (GPCRs), and were found to affect the receptor's Agonist binding Affinity, hence denoted AA-currents. Here we study, employing a combined theoretical-experimental approach, the properties of the AA-currents using the m2-muscarinic receptor (m2R) as a case study. We found that the AA-currents are characterized by a "bump", a distinct rise followed by a slow decline, which appears both in the On and the Off responses. The cumulative features implied a directional behavior of the AA-currents. This forced us to abandon the classical chemical reaction type of models and develop instead a model that includes anisotropic processes, thus producing directionality. This model fitted well the experimental data. Our main findings are that the AA-currents include two components. One is extremely fast, approximately 0.2 ms, at all voltages. The other is slow, 2-3 ms at all voltages. Surprisingly, the slow component includes a process which strongly depends on voltage and can be as fast as 0.3 ms at + 40 mV. The reason that it does not affect the overall time constant of the slow component is that it carries very little charge. The two fast processes are suitable candidates to link between charge movement and agonist binding affinity under physiological conditions.
去极化诱导电荷移动相关电流，类似于通道中的门控电流，最近在 G 蛋白偶联受体 (GPCR) 中得到证实，并被发现影响受体的激动剂结合亲和力，因此被称为 AA 电流。在这里，我们采用理论与实验相结合的方法，以 m2 毒蕈碱受体 (m2R) 为案例研究，研究了 AA 电流的特性。我们发现，AA 电流的特征是“凸起”，即先出现明显的上升，然后缓慢下降，这在 On 和 Off 反应中都出现。累积特征暗示 AA 电流具有方向性。这迫使我们放弃经典的化学反应类型模型，转而开发一种包括各向异性过程的模型，从而产生方向性。该模型很好地拟合了实验数据。我们的主要发现是，AA 电流包括两个成分。一个非常快，大约 0.2 毫秒，在所有电压下。另一个较慢，在所有电压下为 2-3 毫秒。令人惊讶的是，慢成分包括一个强烈依赖电压的过程，在 +40 mV 时可以快至 0.3 毫秒。它不会影响慢分量的整体时间常数的原因是它携带的电荷量非常小。这两个快速过程是在生理条件下将电荷移动和激动剂结合亲和力联系起来的合适候选者。
