title: Falcarindiol allosterically modulates GABAergic currents in cultured rat hippocampal neurons.
abstract: Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA(A) receptor (GABA(A)R) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 μM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts a potent modulatory action on GABA(A)Rs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 3, 50-358 Wrocław, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wyrembek
authors.forename: Roberto
authors.initials: R
authors.lastname: Negri
authors.forename: Przemysław
authors.initials: P
authors.lastname: Kaczor
authors.forename: Marta
authors.initials: M
authors.lastname: Czyżewska
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Jerzy Wladyslaw
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D000818:Animals; D053280:Diynes / Q000737:chemistry / Q000494:pharmacology*; D053281:Enediynes / Q000737:chemistry / Q000494:pharmacology; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000032:analysis* / Q000378:metabolism
chemical_list: D053280:Diynes; D053281:Enediynes; D005233:Fatty Alcohols; D011963:Receptors, GABA-A; C010719:enanthotoxin; C034379:falcarindiol; D005680:gamma-Aminobutyric Acid