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Structure and function of the gap junctions


EMSL Project ID
50562

Abstract

The gap junctions are a class of membrane channel proteins that form direct pathways for cell-to-cell communication. Dynamic mechanisms of channel gating are required to control these communication pathways, while their mis-regulation is associated with a range of pathophysiological conditions, including blindness, deafness, cardiac arrhythmia, stroke and cancers. Our research group is using methods in high-resolution single particle electron cryo-microscopy (CryoEM) to understand the detailed mechanisms of gap junction regulation and how aberrant regulation of inter-cellular communication manifests in disease. The specific aims of this proposal are to: 1) Develop a mechanistic understanding of how low pH-induces closure of gap junction intercellular channels, as observed under ischemic conditions of cell stress. 2) Determine how extracellular Ca2+ is used to gate gap junction hemi-channels. And, 3) Elucidate the mechanism(s) by which annular lipids modulate the gating and conductance properties of gap junctions. Structural and mechanistic insights obtained from these studies are expected to provide broad insight into how intercellular communication is regulated by these ubiquitous cell-to-cell communication pathways. Ultimately, the high-resolution models generated from these studies may enable the development of novel therapeutics targeted at correcting/controlling various gap junction related disease.

Project Details

Start Date
2018-11-01
End Date
2021-01-31
Status
Closed

Team

Principal Investigator

Steve Reichow
Institution
Portland State University

Team Members

Steven Adamou
Institution
Portland State University

Joshua Jarodsky
Institution
Portland State University

Harry Scott
Institution
Oregon Health & Science University

Janette Myers
Institution
Oregon Health & Science University

Susan O'neill
Institution
Portland State University

Jonathan Flores
Institution
Oregon Health & Science University

Irina El Khoury
Institution
Environmental Molecular Sciences Laboratory

Related Publications

Flores JA, Haddad BG, Dolan KA, Myers JB, Yoshioka CC, Copperman J, Zuckerman DM, Reichow SL. Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å. BioRxiv. 2020 April; doi: https://doi-org/10.1101/2020.04.14.036384.