# Structural analysis of the bestrophin anion channel Best2

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,520

## Abstract

Bestrophins are a family of pentameric calcium-activated chloride channels that respond to
intracellular calcium (Ca2+) by allowing the flow of monovalent anions across the membrane.
Bestrophins are activated in the presence of nanomolar to micromolar concentrations of Ca2+ and
exhibit a time- and concentration -dependent inactivation of current. The structural basis behind
activation and subsequent inactivation in response to increasing Ca2+concentrations has not been
fully elucidated at the molecular level. Bestrophins are expressed in a wide variety of tissues, and
often within specialized cell types. Best1 is expressed in the retinal pigmented epithelial (RPE)
cells of the eye and mutations in the BEST1 gene lead to a class of retinal degenerative diseases
called bestrophinopathies. BEST2, on the other hand, is expressed in the basolateral membrane
of the nonpigmented ciliary epithelial (NPE) cells of the eye, where it has been linked to generation
of intraocular pressure, suggesting it may represent a pharmacological target to treat glaucoma.
Sequence analysis of Best1-4 reveals Best2 has a difference in the cytosolic pore constriction, a
region previously implicated in channel gating. The goal of this project is to 1) generate a structural
model to explain Ca2-dependent activation and inactivation in a mammalian Best2 channel,
including electrophysiological analysis and structural analysis of rationionally designed mutants
to test the model, and 2) investigate the structural differences within the cytosolic constriction of
Best2 that distinguish it from other bestrophins. Completion of these aims will inform on the
function of bestrophins throughout the body, and will guide structure-based drug design to
specifically target Best2 and not other bestrophins, which may have potential to treat glaucoma.

## Key facts

- **NIH application ID:** 10020765
- **Project number:** 5F31EY030763-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Aaron Paul Owji
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020765

## Citation

> US National Institutes of Health, RePORTER application 10020765, Structural analysis of the bestrophin anion channel Best2 (5F31EY030763-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020765. Licensed CC0.

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