Pharmacological “cross‐inhibition” of connexin hemichannels and swelling activated anion channels
- 3 October 2008
- Vol. 57 (3), 258-269
- https://doi.org/10.1002/glia.20754
Abstract
The study of ion channels has relied heavily on the use of pharmacological blocking agents. However, many of these agents have multiple effects, which may compromise interpretation of results when the affected mechanisms/pathways mediate similar functions. Volume regulated anion channels (VRAC) and connexin hemichannels can both mediate the release of glutamate and taurine, although these channels have distinct activation stimuli and hemichannels, but not VRAC, are permeable to Lucifer Yellow (LY). It has been reported that some anion channel blockers may inhibit connexin hemichannels. We further examined the effects of classic gap junction/hemichannel blockers and anion channel blockers on these channels. The typical VRAC blockers, NPPB, IAA‐94, and tamoxifen blocked low divalent cation‐induced glutamate and taurine release and LY loading, presumed due to hemichannel opening. The blocking action of these compounds on hemichannels was concentration dependent and fell within the same range where the drugs classically block VRACs. Conversely, carbenoxolone (CBX), the most widely used gap junction/hemichannel blocker, was an effective blocker of VRAC‐mediated glutamate and taurine release, and blocked these channels at similar concentrations at which it blocked hemichannels. The CBX effect on VRACs was verified using astrocytes from connexin 43 knock out (Cx43 KO) animals. In these cells, the hypotonic induced amino acid flux was retained whereas the low divalent cation solution‐induced flux was lost. These results extend our knowledge about “cross‐inhibition” of VRACs and gap junctions/hemichannels by certain pharmacological agents. Given the overlap in function of these two types of channels, great care must be exerted in using pharmacological blockers to identify one channel from the other.Keywords
This publication has 55 references indexed in Scilit:
- Neurons control the expression of connexin 30 and connexin 43 in mouse cortical astrocytesGlia, 2008
- Pannexin1 is part of the pore forming unit of the P2X7 receptor death complexFEBS Letters, 2007
- The Impact of Astrocytic Gap Junctional Coupling on Potassium Buffering in the HippocampusJournal of Neuroscience, 2006
- Release of l-aspartate by reversal of glutamate transportersNeuropharmacology, 2005
- Blockade of Gap Junctions In Vivo Provides Neuroprotection After Perinatal Global IschemiaStroke, 2005
- Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapyGlia, 2005
- Volume-Regulated Anion Channels Are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical PenumbraStroke, 2004
- Ischemia-Induced Brain Damage Depends on Specific Gap-Junctional CouplingJournal of Cerebral Blood Flow & Metabolism, 2002
- Connexin43 null mice reveal that astrocytes express multiple connexinsBrain Research Reviews, 2000
- Scrape-loading and dye transfer: A rapid and simple technique to study gap junctional intercellular communicationExperimental Cell Research, 1987