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Bidirectional Modulation of GABA‐Gated Chloride Channels by Divalent Cations: Inhibition by Ca 2+ and Enhancement by Mg 2+
Author(s) -
Schwartz Rochelle D.,
Wagner Joseph P.,
Yu Xiao,
Martin David
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62030916.x
Subject(s) - muscimol , divalent , chemistry , gabaa receptor , biophysics , inhibitory postsynaptic potential , intracellular , biochemistry , endocrinology , receptor , biology , organic chemistry
Abstract: The effects of the divalent cations Ca 2+ , Sr 2+ , Ba 2+ , Mg 2+ , Mn 2+ , and Cd 2+ were studied on γ‐aminobutyric acid A (GABA A ) responses in rat cerebral cortical synaptoneurosomes. The divalent cations produced bidirectional modulation of muscimol‐induced 36 Cl − uptake consistent with their ability to permeate and block Ca 2+ channels. The order of potency for inhibition of muscimol responses was Ca 2+ > Sr 2+ > Ba 2+ , similar to the order for permeation of Ca 2+ channels in neurons. The order of potency for enhancement of muscimol responses was Cd 2+ > Mn 2+ > Mg 2+ , similar to the order for blockade of Ca 2+ channels in neurons. Neither Ca 2+ nor Mg 2+ 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 Ca 2+ was most likely via an intracellular site of action because additional inhibition could be obtained in the presence of the Ca 2+ ionophore, A23187. This confirms electrophysiologic findings in cultured neurons from several species. In contrast, the effects of Cd 2+ , Mn 2+ , and Mg 2+ may be mediated via blockade of Ca 2+ channels or by intracellular sites, although the results of these studies do not distinguish between the two loci. The effects of Zn 2+ were also studied, because this divalent cation is reported to have widely divergent effects on GABA A responses. In contrast to other studies, we demonstrate that Zn 2+ inhibits GABA A responses in an adult neuronal preparation. Zn 2+ produced a concentration‐dependent inhibition (limited to 40%) of muscimol responses with an EC 50 of 60 μ M . The inhibition of muscimol‐induced 38 Cl − uptake by Zn 2+ was noncompetitive. The effect of Zn 2+ was reduced in the presence of Mg 2+ in a competitive or allosteric manner. The portion of GABA A receptors sensitive to Zn 2+ may reflect a specific subunit composition in cerebral cortex as previously observed for recombinant GABA A receptors in several expression systems. The modulation of GABA A receptor function by Ca 2+ and other divalent cations may play an important role in the development and/or attenuation of neuronal excitability associated with pathologic conditions such as seizure activity and cerebral ischemia.