Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
1. Modulation of GABA(A) receptors by external H(+) was examined in cultured rat sympathetic neurones, and in Xenopus laevis oocytes and human embryonic kidney (HEK) cells expressing recombinant GABA(A) receptors composed of combinations of alpha 1, beta 1, beta 2, gamma 2S and delta subunits. 2. Changing the external pH from 7.4 reduced GABA-activated currents in sympathetic neurones. pH titration of the GABA-induced current was fitted with a pH model which predicted that H(+) interact with two sites (PK(a) values of 6.4 and 7.2). 3. For alpha 1 beta 1 GABA(A) receptors, low external pH (< 7.4) enhanced responses to GABA. pH titration predicted the existence of two sites with PK(a) values of 6.6 and 7.5. The GABA concentration-response curve was shifted to the left by low pH and non-competitively inhibited at high pH (> 7.4). 4. alpha 1 beta 1 gamma 2S receptor constructs were not affected by external pH, whereas exchanging the beta 1 subunit for beta 2 conferred a sensitivity to pH, with predicted PK(a) values of 5.16 and 9.44. 5. Low pH enhanced the responses to GABA on alpha 1 beta 1 delta subunits, whilst high pH caused an inhibition (PK(a) values of 6.6 and 9.9). The GABA concentration-response curves were enhanced (pH 5.4) or reduced (pH 9.4) with no changes in the GABA EC(50). 6. Immunoprecipitation with subunit and epitope-specific antisera to alpha 1, beta 1 and delta subunits demonstrated that these subunits could co-assemble in cell membranes. 7. Expression of alpha 1 beta 1 gamma 2S delta constructs resulted in a 'bell-shaped' pH titration relationship. Increasing or decreasing external pH inhibited the responses to GABA. 8. The pH sensitivity of recombinant GABA(A) receptors expressed in HEK cells was generally in accordance with data accrued from Xenopus oocytes. However, rapid application of GABA to alpha 1 beta 1 constructs at high pH (> 7.4) caused an increased peak and reduced steady-state current, with a correspondingly increased rate of desensitization. 9. Modulation of GABA(A) receptor function was apparently unaffected by the internal pH. Moreover, pH values between 5 and 9.5 did not significantly affect the charge distribution on the zwitterionic GABA molecules. 10. In conclusion, this study demonstrates that external pH can either enhance, have little effect, or reduce GABA-activated responses, and this is apparently dependent on the receptor subunit composition. The potential importance of H(+) sensitivity of GABA(A) receptors is discussed.
Angelotti,
Assembly of GABAA receptor subunits: alpha 1 beta 1 and alpha 1 beta 1 gamma 2S subunits produce unique ion channels with dissimilar single-channel properties.
1993, Pubmed
Angelotti,
Assembly of GABAA receptor subunits: alpha 1 beta 1 and alpha 1 beta 1 gamma 2S subunits produce unique ion channels with dissimilar single-channel properties.
1993,
Pubmed
Antosiewicz,
Prediction of pH-dependent properties of proteins.
1994,
Pubmed
Chen,
Modulation of extracellular pH by glutamate and GABA in rat hippocampal slices.
1992,
Pubmed
Chesler,
Modulation of pH by neuronal activity.
1992,
Pubmed
Chesler,
Stimulus-induced extracellular pH transients in the in vitro turtle cerebellum.
1988,
Pubmed
Chesler,
The regulation and modulation of pH in the nervous system.
1990,
Pubmed
Draguhn,
Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+.
1990,
Pubmed
Eisner,
A novel method for absolute calibration of intracellular pH indicators.
1989,
Pubmed
Evan,
Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product.
1985,
Pubmed
,
Xenbase
Gruol,
Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons.
1980,
Pubmed
Harrison,
Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels.
1994,
Pubmed
Kaila,
Ionic basis of GABAA receptor channel function in the nervous system.
1994,
Pubmed
Kaila,
Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance.
,
Pubmed
Kraig,
Alkaline and acid transients in cerebellar microenvironment.
1983,
Pubmed
Krishek,
Regulation of GABAA receptor function by protein kinase C phosphorylation.
1994,
Pubmed
,
Xenbase
Macdonald,
GABAA receptor channels.
1994,
Pubmed
Mayer,
The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus.
1989,
Pubmed
Mellergård,
The regulation of intracellular pH in cultured astrocytes and neuroblastoma cells, and its dependence on extracellular pH in a HCO3-free solution.
1992,
Pubmed
Mertens,
GABAA receptor populations with novel subunit combinations and drug binding profiles identified in brain by alpha 5- and delta-subunit-specific immunopurification.
1993,
Pubmed
Nakagawa,
gamma-Aminobutyric acid-induced response in acutely isolated nucleus solitarii neurons of the rat.
1991,
Pubmed
Nayeem,
Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis.
1994,
Pubmed
Pasternack,
Influence of extracellular and intracellular pH on GABA-gated chloride conductance in crayfish muscle fibres.
1992,
Pubmed
Pritchett,
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology.
1989,
Pubmed
Rink,
Cytoplasmic pH and free Mg2+ in lymphocytes.
1982,
Pubmed
Saxena,
Assembly of GABAA receptor subunits: role of the delta subunit.
1994,
Pubmed
Shivers,
Two novel GABAA receptor subunits exist in distinct neuronal subpopulations.
1989,
Pubmed
Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed
Sigel,
The effect of subunit composition of rat brain GABAA receptors on channel function.
1990,
Pubmed
,
Xenbase
Smart,
Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc.
1994,
Pubmed
Smart,
A novel modulatory binding site for zinc on the GABAA receptor complex in cultured rat neurones.
1992,
Pubmed
Takeuchi,
Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction.
1967,
Pubmed
Tang,
Modulation of the N-methyl-D-aspartate channel by extracellular H+.
1990,
Pubmed
Traynelis,
Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons.
1990,
Pubmed
Urbanics,
Time course of changes of extracellular H+ and K+ activities during and after direct electrical stimulation of the brain cortex.
1978,
Pubmed
Verdoorn,
Functional properties of recombinant rat GABAA receptors depend upon subunit composition.
1990,
Pubmed
Woodward,
Sensitivity of Xenopus oocytes to changes in extracellular pH: possible relevance to proposed expression of atypical mammalian GABAB receptors.
1992,
Pubmed
,
Xenbase
