Differential modulation of GABAA receptor-channel complex by polyvalent cations in rat dorsal root ganglion neurons.
The effects of divalent and trivalent cations on the gamma-aminobutyric acid (GABA)-induced chloride current were studied with rat dorsal root ganglion neurons in primary culture using the whole-cell configuration of the patch-clamp technique. Lanthanum (La3+) reversibly potentiated the GABA-induced current with a half-maximal effective concentration (EC50) of 231 microM and the maximal potentiation to about 300% of control. La3+ did not seem to compete with chlordiazepoxide, pentobarbital or picrotoxin for binding sites, which indicated that the La3+ binding site was distinct from any of the benzodiazepine, barbiturate and picrotoxin binding sites on the GABA receptor-channel complex. Copper (Cu2+) reversibly suppressed the current induced by GABA with an EC50 of 19 microM in a non-competitive manner. Zinc (Zn2+) and Cu2+ had a very similar action on GABA response in terms of potency and efficacy. The degree of suppression of GABA-induced current by Cu2+ and Zn2+ was not affected by La3+, whereas Cu2+ antagonized the blocking action of Zn2+ in a concentration-dependent manner. Therefore, La3+ does not interfere with the binding site(s) for Cu2+ and Zn2+, whereas Cu2+ and Zn2+ may share a common site. These results are consistent with the presence of at least two distinct binding sites for polyvalent cations on the GABA-receptor channel complex: one for positive regulation by La3+ and the other for negative regulation by Cu2+ and Zn2+. These two sites are likely to be located at or near the external orifice of the chloride channel.
Ma
J Y
JY
Department of Pharmacology, Northwestern University Medical School, Chicago, IL 60611.
Narahashi
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D000535:Aluminum / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D002412:Cations / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018118:Chloride Channels; D003300:Copper / Q000494:pharmacology; D004594:Electrophysiology; D018756:GABA Antagonists; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects*; D007811:Lanthanum / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002412:Cations; D018118:Chloride Channels; D018756:GABA Antagonists; D007473:Ion Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D007811:Lanthanum; D003300:Copper; D000535:Aluminum; D015032:Zinc