Title: Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: Gap junctions versus hemichannels
Authors: Iyyathurai, Jegan ×
D'hondt, Catheleyne
Wang, Nan
De Bock, Marijke
Himpens, Bernard
Retamal, Mauricio A
Stehberg, Jimmy
Leybaert, Luc
Bultynck, Geert #
Issue Date: Dec-2013
Publisher: Elsevier Ltd.
Series Title: Neuropharmacology vol:75 pages:491-505
Article number: S0028-3908(13)00196-2
Abstract: 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 [Ca(2+)], increased intracellular [Ca(2+)], 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 a Special Issue entitled 'Connexin based channels'.
ISSN: 0028-3908
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
× corresponding author
# (joint) last author

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