# Biophysical characterization of the human force-gated ion channel Piezo2

> **NIH NIH F31** · DUKE UNIVERSITY · 2024 · $41,828

## Abstract

ABSTRACT
The force-gated ion channel Piezo2 plays a crucial role in various mechanosensory functions, including light
touch detection, proprioception, urination, blood pressure regulation, and lung inflation. Additionally, gain-of-
function and loss-of function mutations have been implicated in Gordon syndrome, distal arthrogryposis, and
overall deficits in proprioception. Given the crucial role of Piezo2 in physiologically significant mechanosensory
processes and its direct association with human diseases, it is imperative to gain a mechanistic understanding
of how Piezo2 functions as a sensor of mechanical stimuli. Although the physiological roles of Piezo2 are well
understood, its fundamental properties—specifically, the tension-response relationship and gating kinetics—
and how they both are affected by tissue-specific alternative splicing, are unknown.
The overall objective of this proposal is to determine the fundamental biophysical properties of the human
force-gated ion channel Piezo2 and systematically investigate six domains that undergo tissue-specific
alternative splicing to determine their necessity and sufficiency in modifying function. My rationale is that
knowing the biophysical properties of Piezo2 will enable us to understand its physiological roles in distinct
tissues and cell types.
I hypothesize that human Piezo2 and its splice variants exhibit distinct sensitivities and dynamic ranges in
membrane tension sensing and differ in their gating kinetics. The scientific premise for this hypothesis is
based on 1) the fact that Piezo2 is alternatively spliced in a tissue-specific manner, which implies an underlying
difference in function, and 2) my preliminary data demonstrating distinct tension-response relationships in two
Piezo2 splice variants. My research plan will determine the tension-response relationship (Aim1) and gating
kinetics (Aim2) of human Piezo2 and the effects of its six spliced domains on these properties.
The proposed research plan is innovative because it develops two innovative tools: Piezo2 constructs that
allow for a structure-function investigation of spliced domains and a rigorous and unbiased image analysis
program. It then applies these tools to explore two innovative concepts: quantification of the Piezo2 tension-
response relationship and the hypothesis that spliced domains affect both this property and gating kinetics.
The significance of this work is that it provides an understanding of the function and physiology of human
Piezo2. This is essential for rationalizing the purpose of Piezo2 tissue-specific splicing, interpreting structural
data of Piezo proteins, and comprehending the physiological forces, both in intensity and temporal dynamics,
Piezo2 can sense or not.
Its positive impact is that it will identify domains that selectively modulate Piezo2 function, which may become
targets for treating Piezo-related diseases, such as itch, inflammatory pain, and chronic pain.

## Key facts

- **NIH application ID:** 10994388
- **Project number:** 1F31NS139449-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Michael James Sindoni
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,828
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994388

## Citation

> US National Institutes of Health, RePORTER application 10994388, Biophysical characterization of the human force-gated ion channel Piezo2 (1F31NS139449-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10994388. Licensed CC0.

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