title: Promiscuous gating modifiers target the voltage sensor of K(v)7.2, TRPV1, and H(v)1 cation channels.
abstract: Some of the fascinating features of voltage-sensing domains (VSDs) in voltage-gated cation channels (VGCCs) are their modular nature and adaptability. Here we examined the VSD sensitivity of different VGCCs to 2 structurally related nontoxin gating modifiers, NH17 and NH29, which stabilize K(v)7.2 potassium channels in the closed and open states, respectively. The effects of NH17 and NH29 were examined in Chinese hamster ovary cells transfected with transient receptor potential vanilloid 1 (TRPV1) or K(v)7.2 channels, as well as in dorsal root ganglia neurons, using the whole-cell patch-clamp technique. NH17 and NH29 exert opposite effects on TRPV1 channels, operating, respectively, as an activator and a blocker of TRPV1 currents (EC50 and IC50 values ranging from 4 to 40 μM). Combined mutagenesis, electrophysiology, structural homology modeling, molecular docking, and molecular dynamics simulation indicate that both compounds target the VSDs of TRPV1 channels, which, like vanilloids, are involved in π-π stacking, H-bonding, and hydrophobic interactions. Reflecting their promiscuity, the drugs also affect the lone VSD proton channel mVSOP. Thus, the same gating modifier can promiscuously interact with different VGCCs, and subtle differences at the VSD-ligand interface will dictate whether the gating modifier stabilizes channels in either the closed or the open state.
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
authors.forename: Polina
authors.initials: P
authors.lastname: Kornilov
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
authors.forename: Asher
authors.initials: A
authors.lastname: Peretz
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea.
authors.forename: Karam
authors.initials: K
authors.lastname: Son
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
authors.forename: Bosmat
authors.initials: B
authors.lastname: Refaeli
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
authors.forename: Netta
authors.initials: N
authors.lastname: Roz
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
authors.forename: Moshe
authors.initials: M
authors.lastname: Rehavi
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top5 Research Program, Ewha Womans University, Seoul, Korea battali@post.tau.ac.il sunchoi@ewha.ac.kr.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and battali@post.tau.ac.il sunchoi@ewha.ac.kr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Attali
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004008:Diclofenac / Q000031:analogs & derivatives / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism; D051658:KCNQ2 Potassium Channel / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D018408:Patch-Clamp Techniques; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D051658:KCNQ2 Potassium Channel; C000592116:NH17 compound; C000592117:NH29 compound; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D004008:Diclofenac; D004159:Diphenylamine
keywords: KCNQ; capsaicin; vanilloid