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J Neurosci
2006 Mar 22;2612:3357-64. doi: 10.1523/JNEUROSCI.4799-05.2006.
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Contributions of the GABAA receptor alpha6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the alpha6 gene.
Santhakumar V, Hanchar HJ, Wallner M, Olsen RW, Otis TS.
???displayArticle.abstract??? GABAA receptors (GABARs) are heteromultimeric proteins composed of five subunits. The specific subunit composition determines critical properties of a GABAR such as pharmacological sensitivities and whether the receptor contributes to synaptic or extrasynaptic forms of inhibition. Classically, synaptic but not extrasynaptic GABARs are thought to respond to benzodiazepines, whereas the reverse has been suggested for ethanol. To examine the effects of subunit composition on GABAR function in situ, we took advantage of two naturally occurring alleles of the rat gene for GABAR subunit alpha6 (Gabra6(100R) and Gabra6(100Q)). Depending on their subunit partners, these two variants of alpha6 can lead to differential sensitivities to benzodiazepines and ethanol. An examination of synaptic and extrasynaptic GABA-mediated currents in cerebellar granule cells from Gabra6(100R/100R) and Gabra6(100Q/100Q) rats uncovered marked allele-dependent differences in benzodiazepine sensitivity. Unexpectedly, we found that the benzodiazepines flunitrazepam and diazepam enhanced extrasynaptic inhibition mediated by delta subunit-containing GABARs in Gabra6(100Q/100Q) rats. Complementary experiments on recombinant GABARs confirmed that, at subsaturating [GABA], flunitrazepam potentiates alpha6/delta subunit-containing GABARs. Based on data and a simple theoretical analysis, we estimate that the average extrasynaptic [GABA] is approximately 160 nm in perfused slices. These results (1) demonstrate contributions of alpha6 subunits to both synaptic and extrasynaptic GABA responses, (2) establish that delta subunit-containing GABARs are benzodiazepine sensitive at subsaturating [GABA] and, (3) provide an empirical estimate of extrasynaptic [GABA] in slices.
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998, Pubmed
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed Brickley,
Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.
1996,
Pubmed Brickley,
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
2001,
Pubmed Brickley,
CNQX increases GABA-mediated synaptic transmission in the cerebellum by an AMPA/kainate receptor-independent mechanism.
2001,
Pubmed Chadderton,
Integration of quanta in cerebellar granule cells during sensory processing.
2004,
Pubmed Farrant,
Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.
2005,
Pubmed Hamann,
Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex.
2002,
Pubmed Hanchar,
Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity.
2005,
Pubmed
,
Xenbase Hevers,
The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes.
1998,
Pubmed Jechlinger,
Subunit composition and quantitative importance of hetero-oligomeric receptors: GABAA receptors containing alpha6 subunits.
1998,
Pubmed Jones,
Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression.
1997,
Pubmed Korpi,
Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor.
1993,
Pubmed Korpi,
Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor.
1995,
Pubmed
,
Xenbase Leao,
Tonic benzodiazepine-sensitive GABAergic inhibition in cultured rodent cerebellar granule cells.
2000,
Pubmed Mitchell,
Shunting inhibition modulates neuronal gain during synaptic excitation.
2003,
Pubmed Mody,
Distinguishing between GABA(A) receptors responsible for tonic and phasic conductances.
2001,
Pubmed Möhler,
GABA(A)-receptor subtypes: a new pharmacology.
2001,
Pubmed Nusser,
Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells.
2002,
Pubmed Nusser,
Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene.
1999,
Pubmed Nusser,
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells.
1998,
Pubmed Otis,
Modulation of decay kinetics and frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents in hippocampal neurons.
1992,
Pubmed Perrais,
Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses.
1999,
Pubmed Pöltl,
Subunit composition and quantitative importance of GABA(A) receptor subtypes in the cerebellum of mouse and rat.
2003,
Pubmed Rossi,
Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry.
1998,
Pubmed Saxena,
Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms.
1996,
Pubmed Stell,
Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons.
2002,
Pubmed Stell,
Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
2003,
Pubmed Tia,
Developmental changes of inhibitory synaptic currents in cerebellar granule neurons: role of GABA(A) receptor alpha 6 subunit.
1996,
Pubmed Wall,
Competitive GABA(A) receptor antagonists increase the proportion of functional high-affinity alpha6 subunit-containing receptors in granule cells of adult rat cerebellum.
2003,
Pubmed Wall,
Alterations in GABAA receptor occupancy occur during the postnatal development of rat Purkinje cell but not granule cell synapses.
2005,
Pubmed Wall,
Development of action potential-dependent and independent spontaneous GABAA receptor-mediated currents in granule cells of postnatal rat cerebellum.
1997,
Pubmed Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase Wieland,
A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.
1992,
Pubmed
