# GIPC3, multifunctional myosin adaptor in mammalian auditory hair cells

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $579,882

## Abstract

GIPC3, a member of Gα-Interacting Protein, C-terminus (GIPC) family, is known to be essential for
hearing. Eleven mutations in GIPC3, spread throughout its three structural domains, cause inherited
autosomal recessive hearing loss. However, the molecular basis for GIPC3 function in the auditory
system and the mechanisms by which these human mutations result in hearing loss are unknown. We
have recently determined the structure of GIPC3 bound to a prototypical receptor and determined the
molecular mechanism of GIPC3 activation and its subsequent binding to MYO6, the unconventional
myosin that is expressed in the auditory hair cells and is essential for hearing. These biochemical and
structural studies allowed us to predict the effects of known deafness-related mutations in GIPC3 on its
activation and MYO6 binding. We have generated two new mouse models, one that is lacking functional
GIPC3 and another one with a W301X point mutation in Gipc3 that corresponds to a mutation with the
most severe auditory phenotype in humans. This study will explore the central hypothesis that GIPC3 has
a dual role in the auditory hair cells. We hypothesize that in stereocilia GIPC3 is involved in shaping
mechanotransduction and hair bundle structure through its interactions with CDH23/myosin-VIIa and
myosin-XVa, respectively. In the cell body, GIPC3 is essential for apical endocytosis at the pericuticular
neckless region due to its interaction with myosin-VI. All these functions are crucial for normal hearing.
However, the exact molecular mechanisms that determine the resting tension in the mechanotransduc-
tion machinery as well as gradation of stereocilia heights and diameters in the auditory hair cell bundles
are still enigmatic. Likewise, very little is known about molecular mechanisms and even the role of
pericuticular neckless endocytosis in the hair cell function. The expected outcomes of this study are to
uncover (a) the precise mechanism of deafness associated with GIPC3 deficiency and (b) the
physiological role of GIPC3 in hair cell functions, especially in mechanotransduction, formation of the hair
bundle architecture, and endocytosis at the pericuticular neckless. Deciphering the function of GIPC3
protein and its known mutations is a critical step towards the development of therapies for the treatment
and/or prevention of GIPC3-dependent deafness and hearing loss.

## Key facts

- **NIH application ID:** 10073045
- **Project number:** 1R01DC019054-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Gregory I Frolenkov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,882
- **Award type:** 1
- **Project period:** 2020-06-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073045

## Citation

> US National Institutes of Health, RePORTER application 10073045, GIPC3, multifunctional myosin adaptor in mammalian auditory hair cells (1R01DC019054-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073045. Licensed CC0.

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