Bidirectional modulation of GABA-gated chloride channels by divalent cations: inhibition by Ca2+ and enhancement by Mg2+.
The effects of the divalent cations Ca2+, Sr2+, Ba2+, Mg2+, Mn2+, and Cd2+ were studied on gamma-aminobutyric acidA (GABAA) responses in rat cerebral cortical synaptoneurosomes. The divalent cations produced bidirectional modulation of muscimol-induced 36Cl- uptake consistent with their ability to permeate and block Ca2+ channels. The order of potency for inhibition of muscimol responses was Ca2+ > Sr2+ > Ba2+, similar to the order for permeation of Ca2+ channels in neurons. The order of potency for enhancement of muscimol responses was Cd2+ > Mn2+ > Mg2+, similar to the order for blockade of Ca2+ channels in neurons. Neither Ca2+ nor Mg2+ caused accumulation of GABA in the extravesicular space due to increased GABA release or decreased reuptake of GABA by the synaptoneurosomes. The inhibition of muscimol responses by Ca2+ was most likely via an intracellular site of action because additional inhibition could be obtained in the presence of the Ca2+ ionophore, A23187. This confirms electrophysiologic findings in cultured neurons from several species. In contrast, the effects of Cd2+, Mn2+, and Mg2+ may be mediated via blockade of Ca2+ channels or by intracellular sites, although the results of these studies do not distinguish between the two loci. The effects of Zn2+ were also studied, because this divalent cation is reported to have widely divergent effects on GABAA responses. In contrast to other studies, we demonstrate that Zn2+ inhibits GABAA responses in an adult neuronal preparation. Zn2+ produced a concentration-dependent inhibition (limited to 40%) of muscimol responses with an EC50 of 60 microM. The inhibition of muscimol-induced 36Cl- uptake by Zn2+ was noncompetitive.(ABSTRACT TRUNCATED AT 250 WORDS)
Schwartz
R D
RD
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Wagner
J P
JP
Yu
X
X
Martin
D
D
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D015640:Ion Channel Gating; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002121:Calcium Channel Blockers; D002413:Cations, Divalent; D018118:Chloride Channels; D002712:Chlorides; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D008274:Magnesium; D015032:Zinc; D002118:Calcium