title: Mechanisms for resin acid effects on membrane currents and GABA(A) receptors in mammalian CNS.
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.
authors.affiliation: Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Health, Natural and Social Sciences, University of Sunderland, Wharncliffe Street, Sunderland, SR1 3SD, UK.
authors.forename: George
authors.initials: G
authors.lastname: Lees
authors.forename: Leanne
authors.initials: L
authors.lastname: Coyne
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Russell A
authors.initials: RA
authors.lastname: Nicholson