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. 1994 Dec;14(6):599–621. doi: 10.1007/BF02088671

GABA receptor-channel complex as a target site of Mercury, copper, zinc, and lanthanides

Toshio Narahashi 1,2,✉, Jenny Yan Ma 1,3, Osamu Arakawa 1,4, Eitan Reuveny 1,5, Masanobu Nakahiro 1,6
PMCID: PMC11566803  PMID: 7641224

Abstract

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 modulate 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 µM and to 270% of control at 100 µM. 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 µM, 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 µM 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.

Key words: mercury, copper, zinc, lanthanum, lanthanides, GABA receptor channel, chloride channel, dorsal root ganglion

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