Title

The action of Retigabine on KV7 channels activity requires PI(4,5)P2. Society of General Physiologist

ORCiD

Carlos A. Villalba-Galea: 0000-0002-6489-4651

Document Type

Poster

Conference Title/Conference Publication

70th Annual Symposium: Genetic & Animal Models for Ion Channel Function in Physiology and Disease

Organization

Society of General Physiologists

Location

Marine Biological Laboratory, Woods Hole, MA

Conference Dates

September 7-11, 2016

Date of Presentation

9-7-2016

ISSN

2572-6803

Abstract

Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans (Rudzinski et al., 2016). Although the mechanisms of action remains unclear, it is thought that Retigabine facilitates M-current activation by shifting the voltage dependence of the heteromeric KV7.2/KV7.3 channel to more negative potentials (Schenzer et al., 2005; Wuttke et al., 2005; Gunthorpe et al., 2012; Kim et al., 2015). This notion, however, has been recently challenged as the pore domain was identified as the drug’s target (Schenzer et al., 2005; Wuttke et al., 2005; Lange et al., 2009; Kim et al., 2015), suggesting that Retigabine could, instead, stabilize already-activated channels without affecting activation. Supporting this latter idea, we have recently shown that the heteromeric KV7.2/KV7.3 channel has at least two open modes, (OPEN1 and OPEN2), that OPEN2 is more stable than OPEN1, and that Retigabine further stabilizes OPEN2 (Corbin-Leftwich et al., 2016). To further understand this process, we evaluated the role of PI(4,5)P2 in KV7 channels modal behavior. KV7 channels are subject to muscarinic regulation since these channels require PI(4,5)P2 to be active. Thus, pinpointing a potential functional link between Retigabine and PI(4,5)P2 would be essential to comprehend the action of anticonvulsants in patients. Using pharmacological and enzymatic approaches, we have found that the stability of the KV7.2/KV7.3 OPEN2 mode exhibits a higher dependence on PI(4,5)P2 than the OPEN1 mode, suggesting that the affinity for phosphoinositides of this channel changes during activation. Per these findings, we hypothesized that the action of Retigabine would depend on the concentration of PI(4,5)P2 since Retigabine targets the OPEN2mode. Indeed, we found that decreasing the PI(4,5)P2 concentration impairs the ability of Retigabine to further stabilize the OPEN2 mode. Therefore, we conclude that PI(4,5)P2 is required for the action of Retigabine on KV7 channels and can be subject to muscarinic regulation.

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