Stereospecific modulation of GABA(A) receptor function by urocanic acid isomers

A deamination product of histidine, urocanic acid, accumulates in the skin of mammals as tr-ans-urocanic acid. Ultraviolet (UV) irradition converts it to the cis-isomer that is an important mediator in UV-induced immunosuppre ssion. We have recently shown that urocanic acid interferes with the agonis t binding to GABA, receptors. We now report that the effects of urocanic ac id on binding of a convulsant ligand (t-butylbicyclo[S-35]phosphorothionate ) to GABA(A) receptors in brain membrane homogenates are dependent on pH of the incubation medium, the agonistic actions being enhanced at the normal pH of the skin (5.5). Using Xenopus laevis oocytes expressing recombinant r at alpha 1 beta 1 gamma 2S GABA(A) receptors, the low pH potentiated the di rect agonistic action of trans-urocanic acid under two-electrode voltage-cl amp, whereas cis-urocanic acid retained its low efficacy both at pH 5.5 and 7.4. The results thus indicate clear differences between urocanic acid iso mers in functional activity at one putative receptor site of immunosuppress ion, the GABA(A) receptor, the presence of which in the skin remains to be demonstrated. (C) 2000 Elsevier Science B.V. All rights reserved.