Connexin hemichannel (HC)

Connexin hemichannels, also known as connexons, are hexameric transmembrane structures formed by the oligomerization of connexin proteins (Leybaert et al., 2017). While two docked hemichannels from adjacent cells form a gap junction for direct intercellular communication, undocked hemichannels facilitate exchange between the cytosol and the extracellular space (Wang et al., 2013). Under normal physiological conditions, these channels have a low open probability, but they can be triggered by stimuli such as ischemia, inflammation, or mechanical stress (Gajardo-Gómez et al., 2017). Pathological opening leads to the excessive release of pro-inflammatory molecules like ATP and glutamate, which can drive cell death and chronic inflammation in diseases such as Alzheimer's and stroke (Márquez-Miranda et al., 2022). Consequently, hemichannels have emerged as significant therapeutic targets, with research focusing on selective inhibitors that block hemichannel activity while sparing gap junction function (Sáez et al., 2015). Current pharmacological approaches include mimetic peptides and small molecules like tonabersat, which aim to mitigate tissue damage in neurodegenerative and cardiovascular disorders (Laird & Lampe, 2018). These channels are also involved in the propagation of calcium waves and the regulation of cell volume (De Vuyst et al., 2009). Selective targeting remains a challenge due to the high structural homology between hemichannels and gap junctions (Evans et al., 2012). However, the development of 'connexin-mimetic' peptides has shown promise in specifically inhibiting the hemichannel state (Wang et al., 2013). Overall, hemichannels represent a critical junction in the transition from physiological signaling to pathological inflammation.

Other names

ConnexonHalf-channelGap junction hemichannelPannexin channel

Blockade of the hemichannel pore or stabilization of the closed state to prevent the release of pro-inflammatory signaling molecules and maintain ionic homeostasis.