No abstract

The chemical structures of some antidepressants are similar to those of recently described amine-containing ligands of acid-sensing ion channels (ASICs). ASICs are expressed in brain neurons and participate in numerous CNS functions. As such, they can be related to antidepressant action or side effects. We therefore studied the actions of a series of antidepressants on recombinant ASIC1a and ASIC2a and on native ASICs in rat brain neurons. Most of the tested compounds prevented steady-state ASIC1a desensitization evoked by conditioning acidification to pH 7.1. Amitriptyline also potentiated ASIC1a responses evoked by pH drops from 7.4 to 6.5. We conclude that amitriptyline has a twofold effect: it shifts activation to less acidic values while also shifting steady-state desensitization to more acidic values. Chlorpromazine, desipramine, amitriptyline, fluoxetine, and atomoxetine potentiated ASIC2a response. Tianeptine caused strong inhibition of ASIC2a. Both potentiation and inhibition of ASIC2a were accompanied by the slowdown of desensitization, suggesting distinct mechanisms of action on activation and desensitization. In experiments on native heteromeric ASICs, tianeptine and amitriptyline demonstrated the same modes of action as on ASIC2a although with reduced potency.

The action of three dicationic drugs, derivatives of adamantane (IEM-1460 and IEM-1754) and phencyclidine (IEM-1925), on glutamate receptors (GluRs) at the insect neuromuscular junction (Calliphora vicina larva) and on neurons of the freshwater gastropodian mollusc Planorbarius corneus has been studied using the voltage clamp technique. In the presence of concanavalin A complex glutamate-induced currents recorded from molluscan neurons reflected mainly the opening of cationic channels as a result of decreased desensitisation and inhibition of a chloride component. Under these conditions all drugs studied inhibited the stationary component of glutamate-gated cationic currents in a dose-dependent manner (IC50 s were 0.1 ~uM, 1.0 ~lM and 19.2 ~aM for the action of IEM-1925, IEM-1460 and IEM-1754 respectively). The same rank order of potency: IEM-1925 > IEM-1460 > IEM-1754 was observed in both the insect and mollusc. The results of these experiments are compared with those obtained earlier on vertebrate GluRs. Open-channel blocking drugs may help to identify and classify GluRs of invertebrates, and could be used as tools to elucidate the involvement of GluRs in the transmission at certain synapses.

Nitric oxide donors were studied on acid‐sensing channels (ASICs) of rat striatal neurons and CHO cells expressing recombinant receptors. S‐nitroso‐acetyl‐penicillamine (SNAP) potentiate or inhibit ASICs depending on their functional state. It potentiated ASICs after pretreatment with extracellular pH 7.4. When ASICs were partially desensitized by pretreatment with pH 7.0, application of SNAP led to increase of their desensitisization. The potentiating effect of NO on ASICs is explained by an increase of ASIC proton sensitivity, whereas inhibition of ASICs by NO is due to an increase of their steady‐state desensitization. Potentiation and inhibition produced by SNAP had different subunit dependence. The most sensitive to potentiation were ASIC1a/2a and ASIC2a channels while ASIC2a and ASIC3 were the most sensitive to inhibition. Potentiation, produced by SNAP, was prevented by sulphhydryl reagent mercaptoethanol, but it did not affect inhibition produced by SNAP. Thus potentiation and inhibition seems to be mediated by different binding sites. We suppose both effects of SNAP are most probably due to nitrosylation, but not to soluble guanylate cyclase activation, because they were unaffected by ODQ, inhibitor of NO‐sensitive guanylate cyclase, and by 8‐Br‐cGMP, an activator of cGMP‐dependent PKG cascades. Work was supported by grant RFBR/STGI 09‐04‐92662‐Ind‐a.