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Updated: May 30, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Mechanisms for resin acid effects on membrane currents and GABA(A) receptors in mammalian CNS
George Lees1, Leanne Coyne, Jian Zheng
1Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Health, Natural and Social Sciences, University of Sunderland, Wharncliffe Street, Sunderland, SR1 3SD, UK.
Abstract:
Resin acids from bleached wood pulp are toxic to fish. 12,14-Dichlorodehydroabietic acid (12,14-Cl(2)DHA) raises cytoplasmic Ca(2+) in synaptosomes and blocks neural GABA(A) receptors; however, the underlying mechanism remains unclear in these earlier rodent studies. 12,14-Cl(2)DHA (50μM) almost completely blocked native GABA(A) currents (rat cortical cultures) but had no significant effect on picrotoxin-sensitive recombinant human receptors in oocytes (α1, β2 and γ2L: the most prevalent isoforms in mammalian brain). In oocytes, 12,14-Cl(2)DHA failed to produce a calcium-activated chloride current, in contrast to the calcium ionophore ionomycin (10μM). However, in cultured cortical pyramidal cells, both ionomycin and 12,14-Cl(2)DHA produced chloride-selective currents of similar magnitude (presumably secondary to Ca(2+) release). 12,14-Cl(2)DHA was unable to stimulate phosphate labelling of [(3)H ]-inositol in mouse synaptosomes, indicating that the study compound does not cause Ca(2+) release via an IP(3) mechanism. Calcium pump ATPase inhibition also seems unlikely since thapsigargin did not elevate free calcium in synaptosomes. 12,14-Cl(2)DHA clearly blocks GABA(A) currents indirectly: we infer that its toxicity may be secondary to the elevations in cytoplasmic Ca(2+) via an unidentified recognition site (or receptor) found in neuronal cells.
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