ArticleThe Journal of physiology2005
Proton modulation of recombinant GABA(A) receptors: influence of GABA concentration and the beta subunit TM2-TM3 domain.
Article in The Journal of physiology, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 38 citations in OpenAlex.
- Applications of Carbonic Anhydrase Inhibitors in Neurological Disorders, Mechanisms and Therapeutic Potential.Sub-cellular biochemistry · 2026Review
- Massive Activation of GABABiomolecules · 2025Review
- Properties of Acute Activation and Inhibition of the β3 Homomeric GABAACS chemical neuroscience · 2025Article
- Alzheimer's Disease Pathogenic Mechanisms: Linking Redox Homeostasis and Mitochondria-Associated Metabolic Pathways Through Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2).Antioxidants (Basel, Switzerland) · 2025Review
- Acetazolamide: Old drug, new evidence?Epilepsia open · 2022Review
- β subunits of GABACommunications biology · 2022Article
- Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives.Molecules (Basel, Switzerland) · 2021Review
- GABAFrontiers in cellular neuroscience · 2020Article
- Article
- Acute neuroinflammation provokes intracellular acidification in mouse hippocampus.Journal of neuroinflammation · 2016Article
- The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19.British journal of pharmacology · 2016Review
- Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2016Article
- Identification of a novel protein complex containing ASIC1a and GABAA receptors and their interregulation.PloS one · 2014Article
- Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures.The EMBO journal · 2013Article
- Identification of the amino acid residues in the extracellular domain of rat P2X(7) receptor involved in functional inhibition by acidic pH.British journal of pharmacology · 2009Article
- Tracking cell surface GABAB receptors using an alpha-bungarotoxin tag.The Journal of biological chemistry · 2008Article
- Extracellular proton modulates GABAergic synaptic transmission in rat hippocampal CA3 neurons.Brain research · 2007Article
- Modulating inhibitory ligand-gated ion channels.The AAPS journal · 2006Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Regulation of GABA(A) receptors by extracellular pH exhibits a dependence on the receptor subunit composition. To date, the molecular mechanism responsible for the modulation of GABA(A) receptors at alkaline pH has remained elusive. We report here that the GABA-activated current can be potentiated at pH 8.4 for both alphabeta and alphabeta gamma subunit-containing receptors, but only at GABA concentrations below the EC40. Site-specific mutagenesis revealed that a single lysine residue, K279 in the beta subunit TM2-TM3 linker, was critically important for alkaline pH to modulate the function of both alpha1beta2 and alpha1beta2 gamma2 receptors. The ability of low concentrations of GABA to reveal different pH titration profiles for GABA(A) receptors was also examined at acidic pH. At pH 6.4, GABA activation of alphabeta gamma receptors was enhanced at low GABA concentrations. This effect was ablated by the mutation H267A in the beta subunit. Decreasing the pH further to 5.4 inhibited GABA responses via alphabeta gamma receptors, whereas those responses recorded from alphabeta receptors were potentiated. Inserting homologous beta subunit residues into the gamma2 subunit to recreate, in alphabeta gamma receptors, the proton modulatory profile of alphabeta receptors, established that in the presence of beta2(H267), the mutation gamma2(T294K) was necessary to potentiate the GABA response at pH 5.4. This residue, T294, is homologous to K279 in the beta subunit and suggests that a lysine at this position is an important residue for mediating the allosteric effects of both acidic and alkaline pH changes, rather than forming a direct site for protonation within the GABA(A) receptor.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.