Structural basis of AMPA receptor inhibition by trans‐4‐butylcyclohexane carboxylic acid

Abstract

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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…Concurrent screening of octanoic acid derivatives identified 4-BCCA as having anticonvulsant activity in in vitro and in vivo seizure models (Chang et al, 2015b). Crystallographic resolution of 4-BCCA in complex with GluA2 showed that the fatty acid resides at the interface between the M1 and M3 helices of adjacent subunits (Yelshanskaya et al, 2020) (Fig. 41).…”

“…Exogenous Positive and Negative Allosteric Modulators). More recently, X-ray crystallography was used to determine the site of action for noncompetitive inhibition by trans-4butylcyclohexane carboxylic acid (4-BCCA), which binds in the side portals leading from membrane to the ion channel pore (Yelshanskaya et al, 2020), similar to local anesthetics in voltage-gated Na 1 channels.…”

“…These linkers are sites for modulation of receptor function (Section IX. Exogenous Positive and Negative Allosteric Modulators), some of which bind to linkers and alter ionpermeation properties and conductance (Perszyk et al, 2020b;Yelshanskaya et al, 2020). In addition, auxiliary subunits modulate Ca 21 permeability in AMPA receptors (Supplemental Table 2).…”

The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and Ca2+ Permeability of GluN1/GluN2A N-Methyl-d-Aspartate Receptors

“…Alternatively, EU1794 could directly interact with the pore cavity, as has been observed with an AMPA receptor modulator (Yelshanskaya et al, 2020).…”

Using Dictyostelium to Advance Our Understanding of the Role of Medium Chain Fatty Acids in Health and Disease

“…The efficacy of these MCFAs was then validated using both in vitro and in vivo animal seizure models ( Chang et al, 2013 , 2014b ), also providing neuroprotective effects ( Chang et al, 2013 ), and confirming the activity of decanoic acid, 4BCCA (trans-4-butylcyclohexanecarboxylic acid), 4EOA (4-ethyloctanoic acid) and other compounds to provide strong seizure control in multiple in vivo seizure models ( Figure 1 ). Finally, decanoic acid but not ketones was also shown to provide strong seizure-control effects in mammalian in vitro models, through the direct inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one of the main excitatory neurotransmitter receptors in the brain, through a direct and non-competitive manner ( Chang et al, 2016 ; Yelshanskaya et al, 2020 ). Specific ratios of MCFAs, with elevated levels of decanoic acid, were then defined to provide enhanced inhibition of AMPA receptors associated with seizure control, and decanoic acid provided synergistic inhibition of AMPA receptors with another epilepsy treatment targeting AMPA receptors, perampanel, in rodent and human models ( Augustin et al, 2018b ).…”