# Effect of lipid environment on the structure and organization of connexin-46/50 gap junction channels

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary
The lens gap junction channels, composed of connexin-46/50 (Cx46/50), are essential to proper development
and maintenance of transparency in the mammalian eye lens. When channel function is disrupted by inherited
mutations or accumulated posttranslational modifications throughout our lifetimes, cataracts occur. In the
native lens membrane environment that Cx46/50 gap junctions naturally exist, phospholipid and cholesterol
composition is highly dynamic and changes markedly throughout our lifetimes. Functional experiments with
other connexin isoforms (Cx32, Cx26) have demonstrated that the permeability of these channels is sensitive
to unique phospholipid types and cholesterol content. However, because there are no high-resolution
structures of any gap junction channels in a lipid bilayer, the mechanism(s) by which membrane composition
influences the structure and function of gap junctions is totally unclear. Additionally, since gap junctions
predominate in the cell membrane as a higher-order assembly (known as gap junctional plaques), it is totally
unknown how protein-protein or protein-lipid-protein interactions contribute to the supra-molecular organization
of plaque formation/remodeling. To address these gaps in knowledge, the primary objective of this proposal
are: 1) to deconvolute the influence of distinct membrane components on the structure and function of the lens
gap junctions Cx46/50; and 2) to characterize the intimate protein-protein and protein-lipid interactions that
stabilize and organize several channels in the context of gap junctional plaques. The primary method
employed in pursuit of these objectives is single particle cryo-electron microscopy, coupled with lipid nanodisc
technologies and in vitro vesicle-permeability functional studies. Success in these aims are expected to directly
impact our understanding how age-related changes in the membrane lipid environment contribute to age-
related changes in gap junction organization and channel activity. Insights from these studies may be broadly
applicable to understanding how connexin-related diseases may be influenced by associated changes in the
tissue-specific lipid environment (e.g., cataract formation, atherosclerosis, stroke and cancers).

## Key facts

- **NIH application ID:** 9950847
- **Project number:** 5F31EY030409-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Jonathan Alex Flores
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-04-11 → 2022-04-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950847

## Citation

> US National Institutes of Health, RePORTER application 9950847, Effect of lipid environment on the structure and organization of connexin-46/50 gap junction channels (5F31EY030409-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9950847. Licensed CC0.

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