Pi(4,5)P2 Modulates Hysteresis and Pharmacology of KV7 Channels

Abstract

KV7 channels are critical components of the plasma membrane in many excitable cells. The main function of KV7 channels is to contribute to the maintenance of the resting potential, thus regulating cellular electrical excitability. In Central Nervous System, the activity of the heteromeric KV7.2/KV7.3 channel gives rise to M-currents. These K+-currents are subject to muscarinic modulation as the phosphoinositide PI(4,5)P2, a signaling lipid dephosphorylated during muscarinic activity, is required by KV7.2/KV7.3 channels to be functional. On the other hand, Corbin-Leftwich and colleagues (JGP, 2016) have recently reported that the deactivation rate of KV7.2/KV7.3 channels depends on the duration of activation. This observation revealed that this heteromeric channel displays a remarkable hysteretic behavior. In addition, it was shown that these channels have, at least, two open modes and that these modes differ in stability, as deactivation from one mode is slower than the other, and in pharmacology, as the anticonvulsant Retigabine preferentially acts on the slower-deactivating mode. Since, (1) the hysteretic behavior of KV7.2/KV7.3 depends of activity and, in turn, (2) activity depends on PI(4,5)P2, an clear next step was to determine whether PI(4,5)P2 can modulate the effect of the anticonvulsant Retigabine. In addressing this question, here, it is presented that each of the open modes of KV7.2/KV7.3 channels displays distinct apparent affinities for PI(4,5)P2. Also, it was found that decreasing the PI(4,5)P2 concentration either pharmacologically or enzymatically, reduces the effect of Retigabine on channel activity when applied in low doses. Furthermore, here it is shown that the hysteretic behavior of the KV7.2/KV7.3 channels does not emerge from being heteromeric, as the individual components display hysteretic behavior as well. The work presented here provides evidence the leads to propose that muscarinic modulation of M-current is likely dependent on the hysteretic behavior of KV7.2/KV7.3 channels.