# CLC-2 voltage-gated chloride channel structure and ligand recognition

> **NIH NIH R21** · STANFORD UNIVERSITY · 2021 · $432,850

## Abstract

In the central nervous system (CNS), voltage-gated ion channels play central roles in shaping action-potential
firing. The cation-selective voltage-gated channels – sodium (Na+), potassium (K+), and calcium (Ca2+)) channels
– have received intense scrutiny over the past decades. In contrast, the chloride (Cl–)-selective voltage-gated
channel, CLC-2, is less well understood, despite its broad expression in neurons and glia throughout the CNS.
A complete understanding of CLC-2’s contribution to CNS function will include an understanding of CLC-2’s
molecular structure. Structurally, CLC channels possess a unique double-barreled architecture and operate
through distinct gating (opening/closing) mechanisms that differ markedly from those of the well-studied Na+, K+,
and Ca2+ channels. In addition to providing a critical framework for studying CLC-2 channel gating and
permeation mechanisms, another compelling rationale for determining the CLC-2 structure is its value for
understanding ligand interactions and guiding design of small-molecule probes. Such probes would be of great
value in investigations of CLC-2 neurophysiology. Accordingly, the goal of this R21 project is develop expression
and purification protocols for CLC-2 and to use cryo-electron microscopy to determine CLC-2 structures in the
absence and presence of the selective CLC-2 inhibitor AK-42.

## Key facts

- **NIH application ID:** 10391191
- **Project number:** 1R21NS125767-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Merritt C Maduke
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,850
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10391191

## Citation

> US National Institutes of Health, RePORTER application 10391191, CLC-2 voltage-gated chloride channel structure and ligand recognition (1R21NS125767-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10391191. Licensed CC0.

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