Pharmacology of connexins and pannexins

Table summarizing the pharmacological inhibitors of connexin and pannexin channels. For each drug, the range of concentration tested as well as their potency on pannexin channels, and connexin hemichannels and gap junctions is indicated.

DrugCharacteristicsConcentrationMagnitude of inhibitionReferences
MefloquinePrevention and treatment of malaria (many side effects reported). Interacts with a number of ion channels and proteins with nonspecific effects and targets, e.g., neuronal calcium homeostasis, the endoplasmic reticulum, calcium pump, acetylcholinesterase, P-glycoproteins in the blood-brain barrier, connexins pannexins, A2A receptors, potassium, and anion channels.1–10 μM++(S)+(R)Dow et al., 2005; Iglesias et al., 2008, 2009a; Li et al., 2010; Nevin, 2011
Probenecid (Pro)Used in the treatment of gout and hyperuricemia, works by interfering with the kidneys organ anion transporter (OAT). Blocks channel based release of cAMP, cGMP, and ATP from various cell types. Reportedly specific to Panx1 by Silverman et al. (2008).150 μM–1 mM++−/+ (Cx46/Cx50)Hsyu et al., 1988; Paul et al., 1991; Beahm and Hall, 2002; Silverman et al., 2008, 2009; Ma et al., 2009; Li et al., 2010
10Panx1Used experimentally, acts to specifically inhibit Panx1 channels, targeted to the extracellular loop region of Panx1. Some effects demonstrated for Cx46 channel inhibition.100 μM++−/+ (Cx46)Pelegrin and Surprenant, 2006; Wang et al., 2007; Bargiotas et al., 2011; Billaud et al., 2011
18-α/β-Glycyrrhetinic acidDerived from licorice herb. Inhibits several channels, e.g., IKCa/SKCa, voltage-dependent channels, pannexin, and connexin channels.25 μM+++/+++Bruzzone et al., 2005; Ozkan and Uma, 2009; Johnstone et al., 2010; Boedtkjer et al., 2013
CarbenoxoloneGlycyrrhetinic acid derivative. Used in treatment of oral ulcerations and lesions, nonspecific ion channel inhibitor, suppresses hyperpolarization.50–100 μM+++++Sagar and Larson, 2006; Thompson et al., 2006; Iglesias et al., 2008, 2009a; Chekeni et al., 2010; Behringer et al., 2012; Gairhe et al., 2012; Boedtkjer et al., 2013; Zhang et al., 2013
40Gap27, 37,43Gap27Used experimentally to inhibit connexin (Cx37, Cx43) and has been showed to affect pannexin channels. Inhibition of Ca2+ oscillations, depolarization, and contraction of smooth muscle cells300 μM++Dora et al., 1999; Haddock et al., 2006; Pelegrin and Surprenant, 2006; Wang et al., 2007; Islam et al., 2012
Flufenamic acidFenamate, nonsteroidal anti-inflammatory drugs. Nonspecific ion channel inhibitor, including: nonselective cation channels, voltage-gated NA+/K+/ Ca2+ channels, connexins (e.g., Cx46), pannexins (Panx1), and calcium activated channels.100–300 μM−/+++ (reversible)Harks et al., 2001; Bruzzone et al., 2005; Iglesias et al., 2008
Arachidonic acid and eicosatetraynoic acid (ETYA)Nonspecific effects on voltage-gated potassium channels, blocker of connexins (e.g., Cx43) and pannexin channels. Arachidonic acid promotes endothelium-induced vasorelaxation, ETYA inhibits endothelium-dependent vasodilation.100 μM++++++De Mey et al., 1982; Martinez and Saez, 1999; Kehl, 2001; Samuels et al., 2013
OuabainCardiotonic steroid, identified in human blood. Widely used experimentally as a Na+/K+-ATPase inhibitor and inhibitor of connexins (not known for pannexins).100 μM–1 mMn/a−/++Weingart, 1977; Martin et al., 2004; Turner et al., 2004; Aperia, 2007; Boedtkjer et al., 2013
HeptanolAliphatic alcohol, gap junction uncoupler/inhibitor200 μM–3 mM−/+++Takens-Kwak et al., 1992; Garcia-Dorado et al., 1997; Pelegrin and Surprenant, 2006; Nishida et al., 2008; Li et al., 2010; Li et al., 2012b
  • +, Partial inhibition; −/+, conflicting reports; ++, greater than 50% inhibition; −, no effect; +++, complete inhibition; n/a, no information available

  • a R and S represent the two stereoisomers of mefloquine (Iglesias et al., 2009b)

  • b Evidence that heptanol effect is not specific to gap junctions in smooth muscle cells (Chaytor et al., 1997).