Abstract
Colchicine is a plant alkaloid that is widely used as a therapeutic agent. It is widely accepted that colchicine reduces the production of inflammatory mediators mainly by altering cytoskeleton dynamics due to its microtubule polymerization inhibitory activity. However, other lines of evidence have shown that colchicine exerts direct actions on the function of ion channels, which are independent of cytoskeleton alterations. Colchicine is able to modify the function of several pentameric ligand-gated ion channels, including glycine receptors (GlyRs). Previous electrophysiological studies have shown that colchicine act as an antagonist of GlyRs composed by the α 1 subunit. In addition, it was recently demonstrated that colchicine directly bind to the α 3 subunit of GlyRs. Interestingly, other studies have shown a main role of α 3GlyRs on chronic inflammatory pain. Nevertheless, the functional effects of colchicine on the α 3GlyR function are still unknown. Here, by using electrophysiological techniques and bioinformatics, we show that colchicine inhibited the function of the α 3GlyRs. Colchicine elicited concentration-dependent inhibitory effects on α 3GlyRs at micromolar range and decreased the apparent affinity for glycine. Single-channel recordings show that the colchicine inhibition is associated with a decrease in the open probability of the ion channel. Molecular docking assays suggest that colchicine preferentially bind to the orthosteric site in the closed state of the ion channel. Altogether, our results suggest that colchicine is a competitive antagonist of the α 3GlyRs.
Highlights
Colchicine is a tricyclic alkaloid known for their effects over cytoskeleton, acting as a microtubule depolymerizing agent (Slobodnick et al, 2015)
The colchicine potency observed in the a3GlyRs was not different from the IC50 obtained in the a1GlyRs (25 ± 6 mM, Supplementary Figure S1)
Since our data suggest that colchicine is a competitive antagonist of the a3GlyRs, our results suggest that the analgesic effects of colchicine in inflammatory pain are possibly not linked to an enhanced a3GlyRs activity
Summary
Colchicine is a tricyclic alkaloid known for their effects over cytoskeleton, acting as a microtubule depolymerizing agent (Slobodnick et al, 2015). By changing cytoskeleton dynamics through microtubule disruption, colchicine affects cellular processes including neutrophil extravasation, cytokine secretion among others events associated with inflammation (Dalbeth et al, 2014). Based on these properties, it has been approved by the FDA for the treatment of inflammatory diseases in 2009 (Center for Drug Evaluation and Research). Several works have reported the direct effects of colchicine on the function of inhibitory and excitatory pLGICs. Electrophysiological experiments performed in Xenopus oocytes have shown that colchicine acts as a competitive antagonist of GlyRs (Machu, 1998) and of GABAARs (Bueno and Leidenheimer, 1998). Similar to GlyRs and GABAARs, the colchicine inhibition of 5-HT3AR function occurred in the absence of pre-incubation through microtubule-independent mechanisms (de Oliveira-Pierce et al, 2009)
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