GABA receptor-channel complex as a target site of mercury, copper, zinc, and lanthanides.
1. The GABAA receptor-chloride channel complex has been shown to be modulated by a variety of chemicals. Scores of chemicals with diverse and unrelated structures augment the GABA-induced chloride current, while some other chemicals suppress the current. Certain heavy metals and a variety of polyvalent cations increase or decrease the current in a potent and efficacious manner. 2. We have studied the mechanisms whereby mercury, copper, zinc, and lanthanides modulated the GABA system by whole-cell and single-channel patch clamp techniques as applied to the rat dorsal root ganglion neurons in primary culture. 3. Mercuric chloride augmented the GABA-induced current to 115% of control at 0.1 microM and to 270% of control at 100 microM. It also generated a slowly developing inward current carried by a variety of ions. In contrast, methylmercury suppressed the GABA-induced current. The potent stimulation of the GABA system by mercuric chloride is deemed important in mercury intoxication. 4. Copper and zinc suppressed the GABA-induced current with an EC50 of 16 and 19 microM, respectively. They bound to a common site on the external surface of the GABA receptor-channel complex. 5. Lanthanum augmented the GABA-induced current with an EC50 of 230 microM by increasing the affinity of the receptor for GABA. It bound to a site on or near the external surface of the GABA receptor-channel complex which is different from the sites for GABA, barbiturates, benzodiazepines, picrotoxin, and copper/zinc. 6. Six other lanthanides with larger atomic numbers also exerted the same stimulatory effect with their efficacies increasing with the atomic number. 7. Single-channel analyses have revealed that the augmentation of whole-cell current by terbium, a lanthanide, is due to three actions: an increase in the overall mean open time, a decrease in the overall mean closed time, and an increase in the overall mean burst time.
Narahashi
T
T
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Ma
J Y
JY
Arakawa
O
O
Reuveny
E
E
Nakahiro
M
M
D000818:Animals; D000831:Animals, Newborn; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D003300:Copper / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008628:Mercury / Q000494:pharmacology*; D008674:Metals, Rare Earth / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013725:Terbium / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
D018118:Chloride Channels; D008674:Metals, Rare Earth; D011963:Receptors, GABA-A; D013725:Terbium; D003300:Copper; D008628:Mercury; D015032:Zinc