title: Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: gap junctions versus hemichannels.
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 [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'.
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus Gasthuisberg O/N-I Bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Jegan
authors.initials: J
authors.lastname: Iyyathurai
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus Gasthuisberg O/N-I Bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Catheleyne
authors.initials: C
authors.lastname: D'hondt
authors.affiliation: Faculty of Medicine and Health Sciences, Physiology Group, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185 (Block B-Rm 310), B-9000 Ghent, Belgium.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Faculty of Medicine and Health Sciences, Physiology Group, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185 (Block B-Rm 310), B-9000 Ghent, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: De Bock
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus Gasthuisberg O/N-I Bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Himpens
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
authors.forename: Mauricio A
authors.initials: MA
authors.lastname: Retamal
authors.affiliation: Universidad Andres Bello, Laboratorio de Neurobiologia, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Santiago, Chile; Universidad Andres Bello, Centro de Investigaciones Biomédicas, Santiago, Chile.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Stehberg
authors.affiliation: Faculty of Medicine and Health Sciences, Physiology Group, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185 (Block B-Rm 310), B-9000 Ghent, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Leybaert
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Campus Gasthuisberg O/N-I Bus 802, Herestraat 49, BE-3000 Leuven, Belgium. Electronic address: geert.bultynck@med.kuleuven.be.
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D000818:Animals; D001703:Biophysics; D018031:Connexin 43 / Q000737:chemistry / Q000378:metabolism*; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D007473:Ion Channels / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*
chemical_list: D018031:Connexin 43; D007473:Ion Channels; D010455:Peptides
keywords: Brain; C-terminal tail; Connexin; Cytoplasmic loop; Gap junctions; Heart; Hemichannels; Intramolecular interactions; Ischemia; Peptides