title: A novel BK channel-targeted peptide suppresses sound evoked activity in the mouse inferior colliculus.
abstract: Large conductance calcium-activated (BK) channels are broadly expressed in neurons and muscle where they modulate cellular activity. Decades of research support an interest in pharmaceutical applications for modulating BK channel function. Here we report a novel BK channel-targeted peptide with functional activity in vitro and in vivo. This 9-amino acid peptide, LS3, has a unique action, suppressing channel gating rather than blocking the pore of heterologously expressed human BK channels. With an IC50in the high picomolar range, the apparent affinity is higher than known high affinity BK channel toxins. LS3 suppresses locomotor activity via a BK channel-specific mechanism in wild-type or BK channel-humanized Caenorhabditis elegans. Topical application on the dural surface of the auditory midbrain in mouse suppresses sound evoked neural activity, similar to a well-characterized pore blocker of the BK channel. Moreover, this novel ion channel-targeted peptide rapidly crosses the BBB after systemic delivery to modulate auditory processing. Thus, a potent BK channel peptide modulator is open to neurological applications, such as preventing audiogenic seizures that originate in the auditory midbrain.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Scott
authors.affiliation: Department of Chemical &Biomedical Engineering, University of South Florida, Tampa, USA.|Global Center for Hearing &Speech Research, University of South Florida, Tampa, Florida, United States of America.
authors.forename: E J
authors.initials: EJ
authors.lastname: Brecht
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.
authors.forename: A
authors.initials: A
authors.lastname: Philpo
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.
authors.forename: S
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Wu
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Mihic
authors.affiliation: Center for Learning and Memory, University of Texas at Austin, Austin, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Aldrich
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, USA.|Center for Learning and Memory, University of Texas at Austin, Austin, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pierce
authors.affiliation: Department of Chemical &Biomedical Engineering, University of South Florida, Tampa, USA.|Department of Communication Sciences &Disorders, University of South Florida, Tampa, Florida, United States of America.|Global Center for Hearing &Speech Research, University of South Florida, Tampa, Florida, United States of America.
authors.forename: J P
authors.initials: JP
authors.lastname: Walton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001933:Brain Stem / Q000502:physiology; D002460:Cell Line; D005072:Evoked Potentials, Auditory; D006801:Humans; D007245:Inferior Colliculi / Q000187:drug effects* / Q000378:metabolism*; D015640:Ion Channel Gating; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008636:Mesencephalon / Q000502:physiology; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers