# Mechanisms of the calcium-triggered neurotransmitter release machinery in hair cells

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $551,310

## Abstract

Hair cells of the auditory and vestibular systems signal sensory stimuli as graded changes in neurotransmitter
release and employ unique anatomical and molecular components that differ from conventional synapses.
Among the unique molecular features is the apparent lack of reliance on neuronal SNARE proteins and their
various partners. Instead, hair cell exocytosis depends on a large protein called Otoferlin, by unknown
mechanisms. In this proposal, we investigate the unique features of hair cell synaptic transmission using a
combination of molecular biology, electrophysiological approaches in zebrafish, and novel in vitro membrane
fusion assays. In Aim 1 we will determine whether Otoferlin can stimulate membrane fusion using well
established cell-cell fusion assays with engineered cells and determine the requirements for SNAREs, lipids
and calcium in otoferlin-dependent fusion. These experiments will also determine the functional domains
required to mediate membrane fusion. Importantly, this strategy avoids difficulties with purification of Otoferlin
that hindered advances in reconstituting Otoferlin-dependent fusion in the past. In Aim 2, we will measure the
calcium-dependent membrane binding properties of Otoferlin and look for Otoferlin-interacting partners in
native cells. In Aim 3, we use the zebrafish lateral line as a model system explore the role of SNAREs in hair
cell exocytosis. In Aim 4, we test the effectiveness of truncation mutants to rescue synaptic function.
Understanding hair cell synaptic function at the molecular level will ultimately aid in understanding how auditory
information is processed and communicated. Moreover, mutations in Otoferlin lead to DFNB9 form of inherited
deafness and thus study of its function has relevance for human disease. Otoferlin belongs to the ferlin class of
proteins, which include myoferlin and dysferlin, which are also implicated in membrane fusion and human
disease. It is reasonable to expect that what we learn in this project will be instructive for studies with other
ferlins. Lastly, the fundamental understanding of presynaptic processes in these specialized cells will have
broader implications for cellular communication in general and thus, may contribute to our understanding of
various aspects of mental health and neurological disorders.

## Key facts

- **NIH application ID:** 10073199
- **Project number:** 1R01DC019057-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ERDEM KARATEKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $551,310
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073199

## Citation

> US National Institutes of Health, RePORTER application 10073199, Mechanisms of the calcium-triggered neurotransmitter release machinery in hair cells (1R01DC019057-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073199. Licensed CC0.

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