Connexin targeting peptides as inhibitors of voltage- and intracellular Ca2+-triggered Cx43 hemichannel opening

• We review actions of Cx43 targeting peptides on the gating of unapposed hemichannels.
• We highlight electrical and chemical ([Ca2+]i) gating as an interactive network.
• We explore how Cx43 targeting peptides inhibit electrical and [Ca2+]i gating.

Connexins form gap junctions that function as intercellular channels and hemichannels that form a conduit between the cytoplasm and extracellular fluid when open. Peptide inhibitors of connexin channels, especially those identical to defined connexin sequences, are interesting experimental, and possibly also therapeutic tools because they may have better selectivity than general inhibitors like carbenoxolone. Over the past ten years, several peptides have been demonstrated to block hemichannels, including Gap26, Gap27, peptide5, L2 and Gap19; some of these specifically block hemichannels but not gap junctions. Most of these peptides have only recently been investigated towards their actions at the single hemichannel level, bringing up interesting information on how they interact with the connexin protein and how they affect hemichannel gating. Hemichannels can be opened by electrical, mechanical and chemical stimuli. We here review the effect of the prototypic peptides Gap26/27 and L2/Gap19 with specific focus on their inhibition of Cx43 hemichannel opening triggered by positive membrane potentials and changes in intracellular Ca2+ concentration. Both Gap26/27 and L2/Gap19 peptide families block Cx43 hemichannel opening triggered by voltage as well as intracellular Ca2+ stimulation. Interestingly, these peptides as well as intracellular Ca2+ elevation modulate the voltage activation threshold for hemichannel opening, pointing to a common target. Moreover, L2 and Gap19 peptides are part of a sequence on the cytoplasmic loop that acts as a Ca2+/calmodulin interaction site. We here review the interesting network of interactions between Cx43 targeting peptides, voltage gating and intracellular Ca2+ as major modulators of hemichannel function.This article is part of the Special Issue Section entitled ‘Current Pharmacology of Gap Junction Channels and Hemichannels’.