PIP2 mediates functional coupling and pharmacology of neuronal KCNQ channels

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 45; pp. E9702 - E9711
• Main Authors: Kim, Robin Y., Pless, Stephan A., Kurata, Harley T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.11.2017
• Series: PNAS Plus
• Subjects: Activation; Antiepileptic agents; Binding sites; Biological Sciences; Channel gating; Channels; Conductance; Conformation; Coupling; Deactivation; Deceleration; Excitability; Fluorescence; Fluorometers; Fluorometry; KCNQ2 protein; KCNQ3 protein; Neurons; Pharmacology; Phosphatidylinositol 4,5-diphosphate; PNAS Plus; Pore formation; Potassium; Potassium channels (voltage-gated); Prescription drugs; KCNQ channel; epilepsy; potassium channel; electrophysiology; voltage-clamp fluorometry
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1705802114

Retigabine (RTG) is a first-in-class antiepileptic drug that suppresses neuronal excitability through the activation of voltage-gated KCNQ2–5 potassium channels. Retigabine binds to the pore-forming domain, causing a hyperpolarizing shift in the voltage dependence of channel activation. To elucidate how the retigabine binding site is coupled to changes in voltage sensing, we used voltage-clamp fluorometry to track conformational changes of the KCNQ3 voltage-sensing domains (VSDs) in response to voltage, retigabine, and PIP2. Steady-state ionic conductance and voltage sensor fluorescence closely overlap under basal PIP2 conditions. Retigabine stabilizes the conducting conformation of the pore and the activated voltage sensor conformation, leading to dramatic deceleration of current and fluorescence deactivation, but these effects are attenuated upon disruption of channel:PIP2 interactions. These findings reveal an important role for PIP2 in coupling retigabine binding to altered VSD function. We identify a polybasic motif in the proximal C terminus of retigabine-sensitive KCNQ channels that contributes to VSD–pore coupling via PIP2, and thereby influences the unique gating effects of retigabine.