title: Retigabine holds KV7 channels open and stabilizes the resting potential.
abstract: The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine's action remains unknown, previous studies have identified the pore region of KV7 channels as the drug's target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
authors.forename: Aaron
authors.initials: A
authors.lastname: Corbin-Leftwich
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
authors.forename: Sayeed M
authors.initials: SM
authors.lastname: Mossadeq
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
authors.forename: Junghoon
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
authors.forename: Iwona
authors.initials: I
authors.lastname: Ruchala
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298.
authors.forename: Audrey Han Ngoc
authors.initials: AH
authors.lastname: Le
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298 Carlos.VillalbaGalea@vcuhealth.org.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Villalba-Galea
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating; D051658:KCNQ2 Potassium Channel / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials; D010655:Phenylenediamines / Q000494:pharmacology*; D000072417:Protein Domains; D055503:Protein Multimerization; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D010655:Phenylenediamines; C101866:ezogabine