Abstract
Glycine receptors (GlyRs) are chloride-permeable pentameric ligand-gated ion channels. The inhibitory activity of GlyRs is essential for many physiological processes, such as motor control and respiration. In addition, several pathological states, such as hyperekplexia, epilepsy, and chronic pain, are associated with abnormal glycinergic inhibition. Recent studies have pointed out that positive allosteric modulators targeting the GlyR α3 subunit (α3GlyR) displayed beneficial effects in chronic pain models. Interestingly, previous electrophysiological studies have shown that tropeines, which are a family of synthetic antagonists of the serotonin type 3 receptors (5-HT3Rs), potentiate the activity of GlyRs conformed by α1 subunits. However, despite its importance as a pharmacological target in chronic pain, it is currently unknown whether the α3GlyR function is modulated by tropeines. Using electrophysiological techniques and molecular docking simulations, here we show that tropeines are inhibitors of the α3GlyR function. Tropisetron, a prototypical tropeine, exerted concentration-dependent inhibitory effects on α3GlyRs at the low micromolar range. In addition, three other tropeines showed similar effects. Single-channel recordings show that tropisetron inhibition is associated with a decrease in the open probability of the ion channel. Molecular docking assays suggest that tropeines preferentially bind to an agonist-free, closed state of the ion channel. The tropeine binding occurs in a discrete pocket around the vicinity of the orthosteric site within the extracellular domain of α3GlyR. Thus, our results describe the pharmacological modulation of tropeines on α3GlyRs. These findings may contribute to the development of GlyR-selective tropeine derivatives for basic and/or clinical applications.
Highlights
Strychnine-sensitive glycine receptors (GlyRs) are anion-selective neurotransmitter-gated inhibitory ion channels
We first examined the sensitivity of the homomeric α3GlyR to different concentrations of tropisetron, a prototypical tropeine which is widely used as an anti-emetic drug
To obtain additional insights on the chemical determinants associated with the inhibition of α3GlyR by tropeines, we analyzed the effects of three other tropeines on the α3GlyR function
Summary
Strychnine-sensitive glycine receptors (GlyRs) are anion-selective neurotransmitter-gated inhibitory ion channels. Tropeine Actions on Glycine Receptors neurophysiological functions, such as motor coordination, respiratory control, muscle tone, as well as pain processing. The α subunits share a high degree of sequence homology, they exhibit important differences in their biophysical and pharmacological properties as well as in their expression patterns. These specific features are possibly linked to their proposed roles in physiological and pathological states (Lynch, 2009). The binding of the neurotransmitter glycine to the ECD triggers the process of receptor activation, which results in the opening of the ion channel pore
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