Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures

Area of Science:

• Structural biology
• Molecular biophysics
• Cellular physiology

Background:

• Connexins (Cxs) are integral membrane proteins forming hemichannels (HCs) and gap junction channels (GJCs).
• These channels facilitate intercellular and cell-extracellular communication, vital for development and physiological responses.
• Dysfunctional Cx channels are implicated in various pathologies, including inflammation, skin diseases, deafness, neurological disorders, and cardiac arrhythmias.

Purpose of the Study:

• To elucidate the high-resolution structures of Cx isoforms and their gating mechanisms.
• To understand how structural features relate to channel function and dysfunction in pathological conditions.
• To identify potential targets for Cx channel modulation in drug discovery.

Main Methods:

• High-resolution X-ray crystallography and electron cryomicroscopy (cryo-EM) for structural determination.
• Analysis of Cx structures, including transmembrane bundles, extracellular loops, and N-terminal domains.
• Investigating the impact of calcium ions and acidic pH on channel gating.

Main Results:

• Revealed conserved structural features across seven Cx isoforms, including the transmembrane bundle and extracellular loop folds.
• Identified a novel Ca2+-dependent electrostatic gating mechanism in Cx26 GJCs.
• Demonstrated N-terminal domain association as a "ball-and-chain" mechanism for pore blockage under acidic conditions.

Conclusions:

• Structural insights into Cx channels provide a mechanistic understanding of their function and regulation.
• Novel gating mechanisms involving Ca2+ and N-terminal domains are identified, relevant to cellular responses to injury.
• Future studies using advanced cryo-EM and integrated biophysical methods will further unravel Cx channel dynamics and accelerate therapeutic strategies.