A deamination product of histidine, urocanic acid, accumulates in the
skin of mammals as trans-urocanic acid. Ultraviolet (UV) irradition
converts it to the cis-isomer that is an important mediator in
UV-induced immunosuppression. We have recently shown that urocanic acid
interferes with the agonist binding to GABA_A receptors. We now report
that the effects of urocanic acid on binding of a convulsant ligand
(t-butylbicyclo[³⁵S]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 rat
alpha1beta1gamma2S GABA_A receptors, the low pH potentiated the direct
agonistic action of trans-urocanic acid under two-electrode
voltage-clamp, 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 isomers in functional activity at one putative receptor
site of immunosuppression, the GABA_A receptor, the presence of which
in the skin remains to be demonstrated.