title: Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier.
abstract: The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage-sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated K(+) channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltage-sensor trapping mechanism similar to that suggested for scorpion and sea-anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders.
authors: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
authors: Asher
authors: A
authors: Peretz
authors: Liat
authors: L
authors: Pell
authors: Yana
authors: Y
authors: Gofman
authors: Yoni
authors: Y
authors: Haitin
authors: Liora
authors: L
authors: Shamgar
authors: Eti
authors: E
authors: Patrich
authors: Polina
authors: P
authors: Kornilov
authors: Orit
authors: O
authors: Gourgy-Hacohen
authors: Nir
authors: N
authors: Ben-Tal
authors: Bernard
authors: B
authors: Attali
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D051658:KCNQ2 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D014162:Transfection; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D051658:KCNQ2 Potassium Channel; D018377:Neurotransmitter Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D062367:ortho-Aminobenzoates; C001209:fenamic acid