PIP2-Mediated Gating of the Inward Rectifier Potassium Channel Kir2.2

Abstract

Inward-rectifier K+ (Kir) channels are ion channels that transport potassium into the cell. They are essential to maintain the resting membrane potential and to regulate the action potential duration in excitable cells [1]. As a consequence, Kir mutations result in several diseases, such as periodic paralysis or cardiac arrhythmia [1, 2].The activity of Kir channels is regulated by phosphatidylinositol-(4,5)-bisphosphate (PIP2), a negatively charged phospholipid that has been recognized as one of the major regulators of membrane excitability [2]. Recently, the MacKinnon group has solved the crystal structure of Kir2.2 in the apo form [3] and in complex with a PIP2 derivative [4]. PIP2 binding is shown to induce a large conformational change of the linker connecting the transmembrane (TMD) and cytosolic (CTD) domains, as well as the opening of the inner helix bundle crossing (HBC) gate. However, the specific mechanism of Kir activation by PIP2 is not known yet.Here we have investigated the dynamics of PIP2-triggered channel gating by means of molecular dynamics (MD). Simulations have been performed on both the apo and holo states of the channel, embedded in a POPC membrane in the presence of KCl. The trajectories obtained give further insight into how the channel-PIP2 interactions drive the contraction of the linker and the translation of the CTD towards the TMD, resulting in the separation of the helices at the HBC gate. Additional free energy perturbation calculations will be needed to provide an estimate of the binding affinity of PIP2 to the channel and the extent of the cooperativity effect [5].[1] Physiol. Rev. 90:291-366 (2010).[2] Pflugers Arch. 460:321–341 (2010).[3] Science, 326:1668-1674 (2009)[4] Nature (Letter), 477:495-499 (2011)[5] (a) Channels, 2:19-33 (2008). (b) J. Physiol. 586:1833-1848 (2008)