# Expression of Ion Channels in the Auditory System

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $397,382

## Abstract

ABSTRACT
Spinocerebellar Ataxia Type 13 (SCA13) is caused by mutations in KCNC3, the gene that encodes Kv3.1
voltage-dependent potassium channels. This condition results in motor abnormalities and the inability to locate
sounds in space. Kv3.3 is highly expressed in the cerebellum and in auditory brainstem nuclei, including the
calyx of Held presynaptic terminals in the medial nucleus of the trapezoid body (MNTB). Kv3.3 differs from
other closely-related channels in having an extended C-terminal cytoplasmic domain that recruits several
cytoplasmic signaling molecules, including Tank Binding Kinase 1 (TBK1). This enzyme keeps Kv3.3 bound to
Hax-1, a cell survival protein that, when bound to the channel, triggers the formation of a dense actin
cytoskeleton under the plasma membrane. This process is impaired in a Kv3.3 mutant (G592R Kv3.3) that
causes late-onset SCA13. This mutation overstimulates TBK1 activity but prevents the channel from triggering
actin nucleation. The experiments in this proposal will test the hypothesis that TBK1 is required for normal
synaptic transmission and endocytosis of synaptic vesicles because it is a physiological regulator of the
interactions between the Kv3.3 and the underlying actin cytoskeleton. Patch clamp studies will be combined
with imaging and EM immunomicroscopy to test the effects of TBK1 inhibition or manipulation of TBK1 activity
with genetic approaches in cell lines and in the calyx of Held terminals from wild type, Kv3.3-/- and G592R
Kv3.3 animals . Phospho-specific antibodies will be used to determine if TBK1 activity is altered by stimulation
of auditory neurons in brain slice preparations and by acoustic stimulation of intact animals in vivo. Finally, the
specific domains required to couple TBK1 to the Kv3.3/Hax-1 complex will be defined by mutagenesis studies
and by proteomic approaches that identify phosphorylation sites for TBK1 in the channel complex. Our findings
will provide novel insights into the regulation of synaptic transmission in normal and pathological conditions
and will generate new targets for the treatment of diseases such as Spinocerebellar Ataxia Type 13 and other
conditions that affect central auditory processing.

## Key facts

- **NIH application ID:** 10416063
- **Project number:** 5R01DC001919-30
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** LEONARD K KACZMAREK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,382
- **Award type:** 5
- **Project period:** 1993-04-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416063

## Citation

> US National Institutes of Health, RePORTER application 10416063, Expression of Ion Channels in the Auditory System (5R01DC001919-30). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10416063. Licensed CC0.

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