title: Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons.
abstract: Many rapidly firing neurons, including those in the medial nucleus of the trapezoid body (MNTB) in the auditory brain stem, express "high threshold" voltage-gated Kv3.1 potassium channels that activate only at positive potentials and are required for stimuli to generate rapid trains of actions potentials. We now describe the actions of two imidazolidinedione derivatives, AUT1 and AUT2, which modulate Kv3.1 channels. Using Chinese hamster ovary cells stably expressing rat Kv3.1 channels, we found that lower concentrations of these compounds shift the voltage of activation of Kv3.1 currents toward negative potentials, increasing currents evoked by depolarization from typical neuronal resting potentials. Single-channel recordings also showed that AUT1 shifted the open probability of Kv3.1 to more negative potentials. Higher concentrations of AUT2 also shifted inactivation to negative potentials. The effects of lower and higher concentrations could be mimicked in numerical simulations by increasing rates of activation and inactivation respectively, with no change in intrinsic voltage dependence. In brain slice recordings of mouse MNTB neurons, both AUT1 and AUT2 modulated firing rate at high rates of stimulation, a result predicted by numerical simulations. Our results suggest that pharmaceutical modulation of Kv3.1 currents represents a novel avenue for manipulation of neuronal excitability and has the potential for therapeutic benefit in the treatment of hearing disorders.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Maile R
authors.initials: MR
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Lynda
authors.initials: L
authors.lastname: El-Hassar
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Yalan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Autifony SRL, Verona, Italy; and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.affiliation: Autifony SRL, Verona, Italy; and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut; leonard.kaczmarek@yale.edu.
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells; D003198:Computer Simulation; D003412:Cricetulus; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008959:Models, Neurological; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D051670:Shaw Potassium Channels / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: C000622042:AUT1 compound; C000622043:AUT2 compound; D006827:Hydantoins; D018377:Neurotransmitter Agents; D011725:Pyridines; D051670:Shaw Potassium Channels
keywords: Kv3.1 channels; medial nucleus of the trapezoid body