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.
