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 IC50 in 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.

A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo

“…1C). A previous study from our laboratory characterized the ethanol-independent effects of the single peptide LS3 (Scott et al, 2017a). Here, we present a detailed analysis of all 20 peptides (LS1-LS20) in the presence and absence of ethanol.…”

“…Although not as high-throughput, phenotypic screens can select agents with functional activity at a specific molecular target (Kwok et al, 2006) or a specific action, e.g., neuroprotection (Mondal et al, 2018) or antagonizing fetal alcohol syndrome (Wilkemeyer et al, 2003). Previously, we combined phage display and a secondary phenotypic screen in worm to identify a high-affinity modulator of BK channel function (Scott et al, 2017a). In the present study, our challenge was to select a modulator of the effects of another pharmacological agent at a specific target.…”

Developmental plasticity of hearing sensitivity in red-eared sliderTrachemys scripta elegans

“…The ABR thresholds and latencies were determined using visual inspection similar to that previously described [29]. The threshold measurement was defined as the stimulus level below which no repeatable responses could be recognized [30, 31]. In order to reduce artificial error, all turtle ABR thresholds were determined by the same experienced person.…”

Cochlear protein biomarkers as potential sites for targeted inner ear drug delivery

“…These channels play an important role in processing the neural feedback from the brain [18]. Clinically, the BK channel has been investigated as a potential channel involved in a tinnitus pathway [19].…”

“…A 9-amino acid peptide has been identified which binds tightly to BK channels [19] and can be used both to modulate BK channel activity and potentially as a targeting peptide. Collectively, this work provides the foundation for the concept…”