Cys-loop receptor channel blockers also block GLIC.
The Gloeobacter ligand-gated ion channel (GLIC) is a bacterial homolog of vertebrate Cys-loop ligand-gated ion channels. Its pore-lining region in particular has a high sequence homology to these related proteins. Here we use electrophysiology to examine a range of compounds that block the channels of Cys-loop receptors to probe their pharmacological similarity with GLIC. The data reveal that a number of these compounds also block GLIC, although the pharmacological profile is distinct from these other proteins. The most potent compound was lindane, a GABA(A) receptor antagonist, with an IC₅₀ of 0.2 μM. Docking studies indicated two potential binding sites for this ligand in the pore, at the 9' or between the 0' and 2' residues. Similar experiments with picrotoxinin (IC₅₀ = 2.6 μM) and rimantadine (IC₅₀ = 2.6 μM) reveal interactions with 2'Thr residues in the GLIC pore. These locations are strongly supported by mutagenesis data for picrotoxinin and lindane, which are less potent in a T2'S version of GLIC. Overall, our data show that the inhibitory profile of the GLIC pore has considerable overlap with those of Cys-loop receptors, but the GLIC pore has a unique pharmacology.
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Mona
M
Alqazzaz
Andrew J
AJ
Thompson
Kerry L
KL
Price
Hans-Georg
HG
Breitinger
Sarah C R
SC
Lummis
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D001556:Hexachlorocyclohexane / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding; D012299:Rimantadine / Q000494:pharmacology; D054830:Sesterterpenes
D001426:Bacterial Proteins; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D001556:Hexachlorocyclohexane; D010852:Picrotoxin; D012299:Rimantadine; D054830:Sesterterpenes; C022961:picrotoxinin