Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction

Abstract

Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Here we demonstrate that novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b, designed with molecular modeling approach, inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7. Acidification to 5.0 decreases the inhibition efficacy by up to 3 orders of magnitude. The 5b molecule not only shifts pH dependence of ASIC1a activation but also inhibits its maximal evoked response. These findings suggest that compound 5b binds to pH sensor of ASIC1a acting as orthosteric noncompetitive antagonist. At 100 nM, compound 5b completely inhibits induction of long-term potentiation (LTP) in CA3-CA1 but not in MF-CA3 synapses. These findings support the knockout data indicating the crucial modulatory role of ASIC1a channels in the NMDAR-dependent LTP and introduce a novel type of ASIC1a antagonists.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

“…PcTx1 (10 M in saline, 0.5 l per side, Peptide Institute), compound 5b (100 M in saline, 0.5 l per side), and their respective vehicles were microinfused into ACC at a rate of 0.1 l/min. These drug doses were chosen based on the previous literature using the similar pharmacological strategy to study the function of ASIC1a (Buta et al, 2015;Wang et al, 2018), as well as our preliminary experiments and calculations on the diffusion range of the drug in the ACC according to the estimated average volume of this brain region in an adult mouse. Also, we did not observe any obvious neurological deficits in the druginfused animals, indicating the lack of significant side effects at the selected doses.…”

Subtype‐selective inhibition of acid‐sensing ion channel 3 by a natural flavonoid

“…A competitive inhibitor usually binds to the site similar or close to the agonist binding domain (i.e proton sensor in ASICs) to compete with the agonist (i.e proton) for binding. It is not clear whether the known inhibitors for ASIC3 channels to employ this mechanism yet, but it has been strongly suggested that the compounds that inhibit ASIC1a channels at least should partially act as a competitive antagonist . The compound should not only shift the pH dependence of ASIC1a activation but also inhibit its maximal evoked response .…”

“…57 The compound should not only shift the pH dependence of ASIC1a activation but also inhibit its maximal evoked response. 57 The last type is the allosteric inhibitor, which binds to a distinct site from the channel pore or the agonist-binding site to affect coupling of conformational changes to channel gating. Although it is not investigated to discern these possibilities using the compound 11 on ASIC3 channels, the polyphenol compound chlorogenic acid (compound 9) significantly shifted the proton concentration-response curve downward, with a decrease of 41.76 ± 8.65% in the maximum current response to protons but with no significant change in the pH 50 value, 53 suggesting an allosteric mechanism that likely confers the actions of phenolic compounds.…”

Synaptic signals mediated by protons and acid‐sensing ion channels

“…The effect on LTP was questioned (Wu et al, ), but more recent reports confirmed that genetic deletion or pharmacological blockade of ASIC1a greatly reduced the probability of LTP induction in hippocampal CA1 region (Liu et al, ). Similarly, inhibiting ASIC1a channels with 5b, a novel potent orthosteric antagonist of ASIC1a, prevents NMDAR‐dependent LTP (Buta et al, ). Furthermore, Ievglevskyi et al, showed that inhibition of ASIC with 5b leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents and reduces epileptic discharges in a model of epilepsy suggesting that GABAergic neuronal activity may underlie the inhibitory effect exerted through ASIC channels.…”