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Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications
Luc Leybaert1, Paul D Lampe2, Stefan Dhein2
1Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium (L.L.); Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington (P.D.L.); Institute for Pharmacology, University of Leipzig, Leipzig, Germany (S.D.); Department of Pathology and Immunology, Department of Medical Specialization-Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Department of Pediatrics, University of Chicago, Chicago, Illinois (E.C.B.); Department of Anatomy and Cell Biology, University of Western Ontario, Dental Science Building, London, Ontario, Canada (D.W.L.); Cellular and Physiological Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada (C.C.N.); Department of Ophthalmology and The New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (C.R.G.); and Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen, Germany (R.S.) Luc.Leybaert@UGent.be.
Insights
Connexins form channels crucial for cell communication in the heart, blood vessels, and brain. Peptide-based strategies offer new ways to target these connexin channels for therapeutic benefit.
Area of Science:
- Molecular Biology
- Cellular Physiology
- Neuroscience
- Cardiovascular Science
Background:
- Connexins form gap junction and hemichannel proteins essential for intercellular communication.
- These channels play vital roles in coordinating cardiac and vascular function, and neural activity.
- Dysregulation of connexin channels contributes to cardiovascular and neurological diseases.
Purpose of the Study:
- To review the role of connexins and their channels in cardiovascular and neurovascular health and disease.
- To focus on regulatory aspects and identify potential targets for modulating connexin channel function.
- To highlight recent advances in peptide-based approaches for specific connexin channel modulation.
Main Methods:
- Literature review of connexin channel function in physiological and pathological conditions.
- Analysis of existing and emerging therapeutic strategies targeting connexin channels.
- Focus on peptide-based agents for selective modulation of gap junctions and hemichannels.
Main Results:
- Connexin channels are critical for coordinated cell function in multiple organ systems.
- Pathological conditions can disrupt the balance between gap junction and hemichannel activity.
- Previous connexin-targeting agents lacked specificity, causing off-target effects.
Conclusions:
- Peptide-based approaches offer improved specificity for modulating connexin channels.
- These strategies hold promise for preserving gap junction communication and inhibiting hemichannel opening.
- Targeting connexin channels may provide new avenues for mitigating inflammatory signaling in disease.
Abstract:
Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.