Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: gap junctions versus hemichannels

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dc.contributor.authorIyyathuraia, Jegan
dc.contributor.authorD'hondt, Catheleyne
dc.contributor.authorWang, Nan
dc.contributor.authorDe Bock, Marijke
dc.contributor.authorHimpens, Bernard
dc.contributor.authorRetamal, Mauricio
dc.contributor.authorStehberg, Jimmy
dc.contributor.authorLeybaert, Luc
dc.contributor.authorBultynck, Geert
dc.date.accessioned2017-04-06T19:23:35Z
dc.date.available2017-04-06T19:23:35Z
dc.date.issued2013
dc.descriptionCentro de Fisiología Celular e Integrativa
dc.description.abstractAbout 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'.
dc.format.extent1
dc.identifier.citationNeuropharmacology, 2013,75:491-505
dc.identifier.urihttp://hdl.handle.net/11447/1105
dc.identifier.urihttp://dx.doi.org/10.1016/j.neuropharm.2013.04.050
dc.language.isoen_US
dc.publisherElsevier
dc.subjectConnexin
dc.subjectGap junctions
dc.subjectHemichannels
dc.subjectIntramolecular interactions
dc.subjectCytoplasmic loop
dc.subjectC-terminal tail
dc.subjectPeptides
dc.subjectIschemia
dc.subjectBrain
dc.subjectHeart
dc.titlePeptides and peptide-derived molecules targeting the intracellular domains of Cx43: gap junctions versus hemichannels
dc.typeArtículo

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