About a decade ago, the molecular determinants controlling the opening and closing of
Cx43 gap junction channels have been identified. Advanced biophysical approaches revealed a critical role for structural rearrangements in the cytoplasmic loop and dimerization of the C-terminal tail, resulting in binding of the C-terminal tail to the cytoplasmic loop and
Cx43 gap junction channel closure during cellular
acidosis. This has spurred the development of Cx43-mimetic
peptides and
peptidomimetics that interfere with these loop/tail interactions, thereby preventing the closure of
Cx43 gap junctions, e.g. in the heart upon
ischemia. Recently, we found that loop/tail interactions control Cx43-hemichannel activity but with an opposite effect. Binding of the C-terminal tail to the cytoplasmic loop is a requisite for the opening of
Cx43 hemichannels in response to different stimuli, like decreased extracellular [Ca2+], increased intracellular [Ca2+], positive membrane potentials or
ischemia. Strikingly,
peptides that favor the open state of
Cx43 gap junctions like the L2
peptide inhibit Cx43-hemichannel opening. These tools now provide unprecedented opportunities to selectively inhibit
Cx43 hemichannels while maintaining
Cx43 gap junction communication, impossible to achieve with
siRNA or knockdown approaches both affecting gap junctions and hemichannels. These tools not only are very helpful to unravel the role of
Cx43 hemichannels in complex biological systems, but also hold therapeutic potential to counteract excessive Cx43-hemichannel activity like in
ischemia/reperfusion in the brain and the heart or to prevent
Cx43 hemichannel-mediated gliotransmitter release in the basal amygdala during memory consolidation in response to emotional events. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.