GJs arise from the interaction between 2 hemichannels (HCs) of neighboring cells, which in turn are composed of 6 connexin (Cx) proteins (Maes et al., 2014). in connexin or pannexin primary protein structure. In this paper, a state-of-the-art overview is provided on inhibitors of cellular channels consisting of connexins and pannexins with specific focus on their mode-of-action and therapeutic potential. Keywords: Connexin, pannexin, hemichannel, gap junction, inhibitor 1.?Introduction Direct intercellular communication is mediated by gap junctions (GJs), which can exchange a number of small molecules, such as adenosine triphosphate (ATP), glutamate and prostaglandins, as well as ions, including Ca2+, between the cytosolic compartments of adjacent cells (Hertzberg et al., 1981). This flux is called gap junctional intercellular communication (GJIC). GJs arise from the interaction between 2 hemichannels (HCs) of neighboring cells, which in turn are composed of 6 connexin (Cx) proteins (Maes et al., 2014). In recent years, it has become clear that Cx HCs are not merely structural precursors of GJs, as they also can provide a circuit for communication, albeit between the cytosol and the extracellular environment (Kar et al., 2012; Vinken et al., 2011). Today, 21 different Cx types have been identified in a myriad of human and mouse cell types (Table 1), all which share a similar structure consisting Th of 4 transmembrane domains, 2 extracellular loops (EL), 1 cytoplasmic loop (CL), 1 cytoplasmic oocytes (Bruzzone et al., 2005) with RKI-1313 an attenuated functional activity as observed by a decreased dye uptake and currents (Bruzzone et al., 2003). Posttranslational modifications, including phosphorylation, oocytes (Bruzzone RKI-1313 et al., 2005; Locovei et al., 2007) (Table 2). GA affects many different GJs without being Cx subtype specific (Bodendiek & Raman, 2010), but detailed selectivity studies are lacking. Table 2 Chemical-based inhibitors of gap junctions, connexin hemichannels and pannexin channels.(2-APB, 2-aminoethoxydiphenyl borate; Cx, connexin; GA, glycyrrhetinic acid; GABA, -amino butyric acid; GJs, gap junctions; HCs, hemichannels; IP3, inositol triphosphate; NMDA, oocytes (IC50 2 M), Panx1 channels and P2X7 receptors in oocytes (IC50 50 M)Activation of mineralo- and glucocorticoid receptors, inhibition of 11-hydroxysteroid dehydrogenase (IC50 0.26-4.3 M), voltage-sensitive Ca2+ currents (10 M), Cl- conductance (40 M)(Amagaya et al., 1984; Armanini et al., 1983; Armanini et al., 1982; B?hmer et al., 2001; Bruzzone et al., 2005; Davidson & Baumgarten, 1988; Davidson et al., 1986; Eskandari et al., 2002; Locovei RKI-1313 et al., 2007; Matchkov et al., 2004; Su et al., 2007; Walker & Edwards, 1991)CarbenoxoloneGJs in human fibroblasts (IC50 3M), HCs: Cx26 (IC50 21 M) and Cx38 (IC50 34 M) in oocytes, Panx1 channels (IC50 2-5 M)Inhibition of 11-hydroxysteroid dehydrogenase (IC50 5 M), voltage-gated Ca2+ currents (IC50 48 M), P2X7 receptors (IC50 175 nM), NMDA-evoked currents (IC50 104 M)(Bruzzone et al., 2005; Bhler et al., 1991; Bujalska et al., 1997; Davidson & Baumgarten, 1988; Davidson et al., 1986; John et al., 1999; Ma et al., 2009; Pelegrin & Surprenant, 2006; Ripps et al., 2002, 2004; Suadicani et al., 2006)HeptanolGJs in rat glial cells, insect cells, cardiac cells, stomach and pancreas epithelial cells, pancreatic acinar cellsActivation of Ca2+-activated and ATP-sensitive K+ channels (150 M), glycine receptor function, inhibition of voltage-gated Ca2+ channels, kainate receptor-mediated responses, P2X7 receptors(Bernardini et al., 1984; Dlze & Herv, 1983; Dildy-Mayfield et al., 1996; Guan et al., 1997; Johnston et al., 1980; Matchkov et al., 2004; Meda et al., 1986; Suadicani et al., 2006; Weingart & Bukauskas, 1998)OctanolGJs in rat glial cells, insect cells, cardiac cells, stomach and pancreas epithelial cells, pancreatic acinar cells, HCs: Cx50 in oocytes (IC50 177 M)Activation of GABA responses in oocytes (50 M), inhibition of NMDA receptors (100 M), Na+ currents, T-type Ca2+ channels (IC50 122 M)(Bernardini et al., 1984; Dlze & Herv, 1983; Dildy-Mayfield et al., 1996; Eskandari et al., 2002; Guan et al., 1997; Hirche, 1985; Johnston et al., 1980; Meda et al., 1986; Todorovic & Lingle, 1998; Weingart & Bukauskas, 1998)HalothaneGJs in cardiac cells, neonatal rat cardiac myocytes (2 mM), crayfish axons (IC50 28.5 mM), cultured astrocytes (0.1-1 mM), hippocampal slices (2.8 mM)Inhibition of TTX-resistant and TTX-sensitive Na+ channels, excitatory synaptic transmission, G-protein-activated K+ channel currents, muscarinic receptors, NMDA receptors, thromboxane A2 signaling; glutamate receptors(Banks & Pearce, 1999; Beirne et al., 1998; Burt & Spray, 1989; Dildy-Mayfield et al., et al., 1996; Hauswirth, 1969; H?nemann et al., 1998; Jones.