New Mechanism For Voltage Induced Charge Movement Revealed In Gpcrs - Theory And Experiments

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, similar to 0.2ms, at all voltages. The other is slow, 2-3ms at all voltages. Surprisingly, the slow component includes a process which strongly depends on voltage and can be as fast as 0.3ms at + 40mV. 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.