Modulation of voltage-gated potassium channels by phosphatidylinositol-4,5-bisphosphate

Abstract : Voltage-gated potassium (Kv) channels are transmembrane proteins that enable the passive flow of potassium ions across a plasma membrane when the latter is depolarized. They consist of four peripheral voltage sensor domains, responding to the applied voltage, and a central pore domain that encompasses a hydrophilic path for passing ions. The voltage sensors and the pore are coupled, meaning that the activation of the voltage sensors triggers the pore opening, and the open pore promotes the activation of the voltage sensors. Phosphatidylinositol-4,5-bisphosphate (PIP2) is a minor lipid of the inner plasma membrane leaflet. This highly negatively charged lipid was shown to modulate the functioning of several ion channels including members of the Kv family. In particular, application of this lipid to Kv1.2 and Kv7.1, two homologous channels, enhances their ionic current. However, while Kv1.2 is able to open without PIP2, in the case of Kv7.1, this lipid is absolutely required for opening. Additionally, in Kv1.2, PIP2 induces a loss of functioning, which is manifested by delayed motions of the voltage sensors. So far, the mechanism underlying the Kv channels modulation by PIP2 remains unknown. In the present manuscript, we attempt to shed light on this mechanism using molecular dynamics (MD) simulations combined with experiments, which was undertaken by our collaborators. Using unconstrained MD simulations, we have identified potential PIP2 binding sites in Kv1.2. In one of these sites, PIP2 interacts with the channel in a state-dependent manner forming salt bridges either with the voltage sensor or with the pore. Based on these findings, we propose a model rationalizing the known experimental data. Further, we aimed to estimate the loss of functioning effect induced by PIP2 on the Kv1.2 voltage sensors. In particular, we have calculated the free energy of the first two transitions along the activation path in the presence and absence of this lipid. We found that PIP2 affects both the relative stability of the voltage sensor states and the free energy barriers separating them. Finally, we studied the interactions between PIP2 and another member of the Kv family, the cardiac channel Kv7.1. In the PIP2 binding site that we have identified for this channel, the interaction between positive residues of Kv7.1 and the lipid was state-dependent, as in the case of Kv1.2. This state-dependent interaction, however, is prominent for coupling between the voltage sensors and the pore, which is otherwise weakened due to electrostatic repulsion of some positive residues. These findings are in a good agreement with the experimental data obtained by our collaborators
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Marina Kasimova. Modulation of voltage-gated potassium channels by phosphatidylinositol-4,5-bisphosphate. Other. Université de Lorraine, 2014. English. ⟨NNT : 2014LORR0204⟩. ⟨tel-01751176⟩

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