ArticleThe Journal of physiology2007
Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation.
Article in The Journal of physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Region and layer-specific expression of GABAFrontiers in cellular neuroscience · 2024Article
- Pregnenolone sulfate analogues differentially modulate GABABritish journal of pharmacology · 2023Article
- Mutations at the M2 and M3 Transmembrane Helices of the GABAACS chemical neuroscience · 2021Article
- Physiological role for GABANature communications · 2021Article
- Computational and Molecular Properties of Starburst Amacrine Cell Synapses Differ With Postsynaptic Cell Type.Frontiers in cellular neuroscience · 2021Article
- Coupling structure with function in acid-sensing ion channels: challenges in pursuit of proton sensors.The Journal of physiology · 2021Review
- Dravet syndrome-associated mutations inBrain communications · 2021Article
- GABA beyond the synapse: defining the subtype-specific pharmacodynamics of non-synaptic GABAThe Journal of physiology · 2018Article
- Comparison of αβδ and αβγ GABAPharmacological research · 2018Review
- Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed α1β2γ2L GABA(A) Receptors.Molecular pharmacology · 2016Article
- Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity.Journal of cellular and molecular medicine · 2015Article
- α1F64 Residue at GABA(A) receptor binding site is involved in gating by influencing the receptor flipping transitions.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Multiple tyrosine residues at the GABA binding pocket influence surface expression and mediate kinetics of the GABAA receptor.Journal of neurochemistry · 2013Article
- Influences on blockade by t-butylbicyclo-phosphoro-thionate of GABA(A) receptor spontaneous gating, agonist activation and desensitization.The Journal of physiology · 2012Article
- Homeostatic strengthening of inhibitory synapses is mediated by the accumulation of GABA(A) receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Article
- Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus.Frontiers in cellular neuroscience · 2011Article
- Barbiturates require the N terminus and first transmembrane domain of the delta subunit for enhancement of alpha1beta3delta GABAA receptor currents.The Journal of biological chemistry · 2010Article
- Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.The Journal of physiology · 2010Article
- Targeting ligand-gated ion channels in neurology and psychiatry: is pharmacological promiscuity an obstacle or an opportunity?BMC pharmacology · 2010Article
- Context dependent benzodiazepine modulation of GABA(A) receptor opening frequency.Current neuropharmacology · 2010Article
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Authors and funding
5 authors.
Funding
Abstract
The time course of inhibitory postsynaptic currents (IPSCs) reflects GABA(A) receptor deactivation, the process of current relaxation following transient activation. Fast desensitization has been demonstrated to prolong deactivation, and these processes have been described as being 'coupled'. However, the relationship between desensitization and deactivation remains poorly understood. We investigated the 'uncoupling' of GABA(A) receptor macroscopic desensitization and deactivation using experimental conditions that affected these two processes differently. Changing agonist affinity preferentially altered deactivation, changing agonist concentration preferentially altered macroscopic desensitization, and a pore domain mutation prolonged deactivation despite blocking fast desensitization. To gain insight into the mechanistic basis for coupling and uncoupling, simulations were used to systematically evaluate the interplay between agonist affinity, gating efficacy, and desensitized state stability in shaping macroscopic desensitization and deactivation. We found that the influence of individual kinetic transitions on macroscopic currents depended not only on model connectivity, but also on the relationship among transitions within a given model. In addition, changing single rate constants differentially affected macroscopic desensitization and deactivation, thus providing parsimonious kinetic explanations for experimentally observed uncoupling. Finally, these findings permitted development of an algorithmic framework for kinetic interpretation of experimental manipulations that alter macroscopic current properties.
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