# Structure and function of chloride channels, transporters and scramblases

> **NIH GM R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2026 · $567,825

## Abstract

ABSTRACT
Anion channels, active transporters, and lipid scramblases are central players in human physiology. These
integral membrane proteins play key roles in physiology where they control a panoply of processes, ranging from
epithelial salt reabsorption and neuromuscular excitability to blood coagulation, membrane fusion and repair. My
long-term objective is to understand the molecular mechanisms of gating and regulation of two families of
membrane transport proteins, the voltage-gated CLCs and the Ca2+-activated TMEM16s. An unexpectedly
shared property of CLCs and TMEM16s is that they display remarkable functional diversity within conserved
structural frameworks. Whereas both families were originally identified as chloride channels, subsequent work
revealed that many CLCs are H+-coupled active transporters and most TMEM16s are dual-function phospholipid
scramblases and non-selective ion channels. Missense mutations that cause dysfunction in members of both
families cause inheritable disorders of bone, kidney, brain, and muscle. Thus, CLCs and TMEM16s are priority
targets for the development of pharmacological tools to treat these disorders. However, a lack of understanding
of how CLCs and TMEM16s function at the atomic level significantly hinders the development of such tools. For
example, the rational design of compounds to treat these disorders is hampered by the lack of structural
information on the specific conformations stabilized by the gain or loss of function mutations. The overarching
goal of our proposal is to understand at the atomic level how CLCs and TMEM16s are regulated by physiological
stimuli and to elucidate how disease-causing mutations alter their structure-function relationships. To this end,
we will focus on the CLC-1 channel which is mutated in myotonia congenita, a rare muscle disorder, and on the
TMEM16E scramblase, which is mutated in limb girdle muscular dystrophy and in gnathodiaphyseal dysplasia,
a rare bone disorder. The limited unde

## Key facts

- **NIH application ID:** 11249575
- **Project number:** 5R35GM152012-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alessio  Accardi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $567,825
- **Award type:** 5
- **Project period:** 2024-01-01T00:00:00 → 2028-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11249575

## Citation

> US National Institutes of Health, RePORTER application 11249575, Structure and function of chloride channels, transporters and scramblases (5R35GM152012-03). Retrieved via AI Analytics 2026-05-18 from https://api.ai-analytics.org/grant/nih/11249575. Licensed CC0.

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