Российская академия наук


NEW LIGANDS AND MODULATORS OF ACID-SENSING ION CHANNELS



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NEW LIGANDS AND MODULATORS OF ACID-SENSING ION CHANNELS

Sharonova I.N., Bukanova J.V., Skrebitsky V.G.

Research Center of Neurology Russian Academy of Medical Sciences, Moscow, Russia,

sharonova.irina@gmail.com
The acid sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviours including fear, anxiety, pain, depression, as well as learning and memory. The role of the ASIC in behaviour associated with anxiety and fear is shown in experiments with a blockade of the genes that encode ASIC1а channels, which results in decreased fear conditioning and innate fear responses in mice (Coryell et al., 2007). It was also demonstrated that ASIC inhibition produces anxiolytic-like effects in some behavioural models (Dwyer et al., 2009). These observations allow to consider ASIC as a new drug target for the treatment of anxiety disorders. For treatment of anxiety disorders one use different pharmacological agents including the antipsychotic drugs. In this study, we investigated the ability of certain antipsychotic drugs interact with proton-gated channels in central neurons.

Experiments were carried out on cerebellar Purkinje cells acutely isolated from young rat cerebellum. Proton-gated currents were recorded using whole cell patch-clamp and fast perfusion techniques. Сoapplication of acid solution with pH 6.5 (about an IC50) and chlorpromazine (CPZ) produced the inhibition of proton-gated current. The degree of ASIC current suppression by CPZ was dependent both on the drug concentration and the duration of its exposure. Preapplication of chlorpromazine in concentrations of 1-100 μM during 120 s produced the inhibition of current evoked by acid solution (pH 6.5) with an IC50 of 12 µM. Another phenothiazine derivative trifluoperazine (10 µM) applied in the perfusion medium during 5 min caused the decrease of proton-activated current by 38%. Atypical antipsychotic drug clozapine (10 μM) reduced the current amplitude by 29%. The most effective inhibitory action was identified with haloperidol, which blocked the proton-activated currents with an IC50 of about 3 μM. Recently it was discovered a direct interaction between the σ-receptor and the ASIC channels (Camally et al., 2010). Taking into account that CPZ and haloperidol are ligands of σ-receptors, it can be assumed that their influence on the ASIC channels is carried out through interaction with σ-receptors.



The present experiments demonstrate that some antipsychotic drugs at low micromolar concentrations can suppress the activity of proton-gated currents. The functional antagonism of these drugs at ASICs may contribute to their antipsychotic and anxiolytic efficacy and may constitute a not yet recognized pharmacological principle of these drugs. As a whole, ASICs modulators represent a new class of therapeutic agents for neuropsychiatric disorders.

The work was supported by RFBR (grant 11-04-00890) and Grant of the President of the Russian Federation for support of leading scientific schools № NSH-3598.2012.4.

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