Molecular Mechanisms Underlying Membrane Potential-Mediated Regulation of Neuronal K(2P)2.1 Channels

The activity of background K2P channels adjusts the resting membrane potential to enable plasticity of excitable cells. Here we have studied the regulation of neuronal human K2P2.1 (KCNK2, TREK-1) channel activity by resting membrane potential. When heterologously expressed in Xenopus laevis oocytes, K2P2.1 currents gradually increased several fold at hyperpolarizing potentials and declined several fold at depolarizing potentials, with a midpoint potential of −60 mV. As K2P channels are not equipped with an integral voltage sensor, we sought extrinsic cellular components that could convert changes in the membrane electrical field to cellular activity that would indirectly modify K2P2.1 currents. K2P2.1 voltage sensitivity was found not to be mediated by the activity of either voltage activated calcium channels, the Xenopus voltage sensitive proton channel (Xl-Hv) or the Xenopus voltage sensor-containing phosphatase (Xl-VSP). On the other hand, we report that membrane depolarization activated the Gq protein-coupled receptor pathway, in the apparent absence of ligand, resulting in phosphatidylinositol-4,5-bisphosphate (PIP2) depletion through the action of phospholipase C. Our results suggest a novel mechanism in which an indirect pathway confers membrane potential regulation onto channels that are not intrinsically voltage-sensitive to enhance regulation of neuronal excitability levels. The ability of these proteins to operate without any external ligand enhances plasticity at the single cell level, independent of higher regulatory pathways at the tissue or even the organism levels.