Research Article: New Mechanism for Voltage Induced Charge Movement Revealed in GPCRs – Theory and Experiments

Date Published: January 22, 2010

Publisher: Public Library of Science

Author(s): Assaf Zohar, Noa Dekel, Boris Rubinsky, Hanna Parnas, Raya Khanin.

Abstract: 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, , at all voltages. The other is slow, at all voltages. Surprisingly, the slow component includes a process which strongly depends on voltage and can be as fast as at . 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.

Partial Text: Voltage gated channels were shown to exhibit charge movement associated currents, gating currents (GCs), already more than 30 years ago [1]. Since then, an overwhelming amount of experimental data was accumulated [2]–[6]. This data supplemented by mathematical models [7]–[10] indicates that voltage induced reorientation of electric charge within the channel protein produces a conformational change in the protein which leads to channel opening.

We examined several models to their ability to account for the main characteristic features of the AA-currents. We found that only a non-linear model with rate constants that guarantee directionality can match the experimental results.



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