Dietary acetylenic oxylipin falcarinol differentially modulates GABA_A receptors

The dietary oxylipins falcarinol (1a) and falcarindiol (1b) trap thiols by direct nucleophilic addition to their diyne system, but despite this, only falcarinol (1a) is a reversible agonist of cannabinoid receptors, providing a rationale for comparing their activity also on other neuronal targets. Because GABA_A receptors (GABA_ARs) are exquisitely sensitive to polyacetylenic oxylipins in terms of either potentiation (falcarindiol, 1b) or inhibition (oenanthotoxin, 2a), the activity of 1a was investigated on synaptic (α₁β₂γ_2L) and extrasynaptic (α₁β₂δ and α₁β₂) subtypes of GABA_ARs. Falcarinol (1a) significantly enhanced the amplitude of currents mediated by α₁β₂γ_2L receptors, but this effect was associated with a use-dependent block. Conversely, α₁β₂ receptors were inhibited without any sign of use-dependent block for the entire range of concentrations tested (1-10 μM). Interestingly, responses mediated by α₁β₂δ receptors, showing no or very little macroscopic desensitization, were strongly potentiated by 1a, exhibiting a fading reminiscent of macroscopic desensitization. When compared to the activity of falcarindiol (1b), falcarinol (1a) showed a higher affinity for GABA_ARs and, overall, a substantially different profile of pharmacological action. Taken together, the present data support the view that modulation of GABA_ARs might underlie the insecticidal and sedative activity of falcarinol (1a).