# Investigating the molecular mechanism of slow adaptation

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2022 · $155,500

## Abstract

Project Summary/Abstract
The mechano-electrical transduction (MET) process allows the transduction of mechanical information from
sound and head movements into electrical signals, and it is a fundamental step in cochlear and vestibular
system function. MET takes place at the level of the hair bundle and is mediated by tip links, extracellular
proteins connecting shorter stereocilia to adjacent taller stereocilia. A positive deflection of the hair bundle
(toward the tallest row of stereocilia) increases tip-link tension, which increases the open probability of MET
channels. During a sustained displacement, the receptor current peaks then decays, indicating a gradual
decrease in MET channel open probability. This particular process is called "adaptation" and is extremely
important because it shifts the operating range of the MET process to preserve the sensitivity of the system.
 A decades-old hypothesis proposed that slow adaptation, which operates with a time constant on the
order of 10 ms or more, requires Ca2+ entry through the MET channels and the activity of myosin motors to
modulate the tip-link position on taller stereocilia. The major piece of evidence for the motor model is the
presence, during the stimulation, of a creep (a continued movement in the direction of a step-like force
stimulus) in the hair bundle motion with a similar time course as slow adaptation. However, methodological
difficulties have contributed to the limited experiments that test the motor model hypothesis. Using cochlear
and vestibular hair cells of mice, rats, and gerbils, we confirmed that in mammals, slow adaptation requires
Ca2+ and myosin motors, and we assessed that modulating adaptation does not affect hair-bundle creep.
Therefore, adaptation does not involve the movement of the upper tip-link insertion challenging a critical piece
of evidence upholding the motor model.
 Using electrophysiological recording in vestibular and cochlear hair cells, I will test a new hypothesis
where phospholipids are essential for slow adaptation. In particular, studies in rats and frogs have shown that
the phospholipid PIP2 affects MET channel proprieties, and recent data demonstrate that TMIE is an essential
subunit of the MET channel and mediates interactions with PIP2 to modulate channel function. I will test if PIP2
is necessary for slow adaptation in cochlear and vestibular hair cells, and I will test its interplay with myosin
motors. My results will allow me to determine the underlying molecular mechanism of slow adaptation in
mammals, the key process that preserves the sensitivity of the system and allows us to detect a wide range of
sound intensities with extremely high precision.

## Key facts

- **NIH application ID:** 10475229
- **Project number:** 5R21DC019701-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Giusy A Caprara
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $155,500
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475229

## Citation

> US National Institutes of Health, RePORTER application 10475229, Investigating the molecular mechanism of slow adaptation (5R21DC019701-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475229. Licensed CC0.

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