Molecular and Functional Diversity of the Expanding GABA‐A Receptor Gene Family

Whiting, Paul J.; Bonnert, Timothy P.; McKernan, Ruth M.; Farrar, Sophie J.; Bourdellès, B. Le; Heavens, R.P.; Smith, David W.; Hewson, Louise; Rigby, Michael; Sirinathsinghji, D.J.S.; Thompson, Sally A.; Wafford, Keith A.

doi:10.1111/j.1749-6632.1999.tb11341.x

Cited by 317 publications

(212 citation statements)

References 44 publications

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“…Ionotropic GABA receptors can be categorized into GABA A and GABA C receptors based on their subunit compositions and pharmacological properties (Bormann, 2000). Nineteen GABA receptor subunits have been cloned from rats, which include α1-6, β1-3, γ1-3, ρ1-3, δ, θ, ε, and π ( Whiting et al, 1999). We have recently identified the GABA A receptor π subunit as a novel alveolar epithelial type II cell marker (Chen et al, 2004b).…”

Section: Nih Public Accessmentioning

confidence: 99%

Ionotropic GABA receptor expression in the lung during development

Jin

Guo

Sun

et al. 2008

Gene Expression Patterns

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Cl − transport is essential for lung development. Because gamma-aminobutyric acid (GABA) receptors allow the flow of negatively-charged Cl − ions across the cell membrane, we hypothesized that the expression of ionotropic GABA receptors are regulated in the lungs during development. We identified 17 GABA receptor subunits in the lungs by real-time PCR. These subunits were categorized into 4 groups: Group 1 had high mRNA expression during fetal stages and low in adults; Group 2 had steady expression to adult stages with a slight up-regulation at birth; Group 3 showed an increasing expression from fetal to adult lungs; and Group 4 displayed irregular mRNA fluctuations. The protein levels of selected subunits were also determined by Western blots and some subunits had protein levels that corresponded to mRNA levels. Further studied subunits were primarily localized in epithelial cells in the developing lung with differential mRNA expression between isolated cells and whole lung tissues. Our results add to the knowledge of GABA receptor expression in the lung during development. Keywordslungs; ionotropic GABA receptor; fetal lung development; chloride homeostasis; lung fluid transport; real time PCR; gene expression; alveolar epithelial cells RESULTS AND DISCUSSION SignificanceCl − channels play an important role in the lung throughout an animal's life. During the fetal stages, the lung is a fluid-secreting organ. The main driving force for fluid secretion is the active secretion of Cl − into the developing lungs. Therefore, Cl − channels are indispensable for fetal lung development and morphogenesis (Folkesson et al., 1998;Olver et al., 2004;Bland and Nielson, 1992). On the other hand, the adult lung is air-filled and maintains a "dry" state. The apical surface is covered by a thin layer of alveolar surface fluid. This layer of fluid is required for the proper air exchange and airway defenses. Cl − channels are also essential for maintaining the composition and volume of the alveolar surface fluid (Brochiero et al., 2004 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Several Cl − channels have previously been studied in the lung. The cystic fibrosis transmembrane conductance regulator (CFTR) (Harris et al., 1991), the voltage-gated Cl − channels, ClC2 (Thiemann et al., 1992), ClC3 (Lamb et al., 2001), and ClC5 (Edmonds et al., 2002, and Na + -K + -Cl − cotransporter (NKCC) (Rochelle et al., 2000) have been detected in fetal lungs, distal airway epithelial cells and alveolar epithelial cells. Some of the channels have been shown to be involved in fluid homeostasis i...

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Section: Nih Public Accessmentioning

confidence: 99%

Ionotropic GABA receptor expression in the lung during development

Jin

Guo

Sun

et al. 2008

Gene Expression Patterns

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“…To date, seven subunit families have been cloned, and many of these families have multiple subtypes. Six α subtypes, three β subtypes, three γ subtypes, and one member each in the δ, ε, π and θ subunit families have been found in mammalian species (Whiting et al, 1999). Formation of receptors with properties similar to those of native receptors appears to require a combination of at least an α, β, and a tertiary (γ, δ, ε, π or θ) subunit.…”

Section: Introductionmentioning

confidence: 99%

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

Picton

Fisher

2007

Brain Research

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The GABA A receptors (GABARs) are chloride-permeable ligand-gated ion channels responsible for fast inhibitory neurotransmission. These receptors are structurally heterogeneous, and in mammals can be formed from a combination of sixteen different subunit subtypes. Much of this variety comes from the six different α subunit subtypes. All neuronal GABARs contain an α subunit, and the identity of the α subtype affects the pharmacological properties of the receptors. The expression of each of the different α subtypes is regulated developmentally and regionally and changes with both normal physiological processes such development and synaptic plasticity, and pathological conditions such as epilepsy. In order to understand the functional significance of this structural heterogeneity, we examined the effect of the α subtype on the receptor's response to GABA. Each of the six α subtypes was transiently co-expressed with the β3 and γ2L subunits in mammalian cells. The sensitivity to GABA was measured with whole-cell recordings. We also determined the activation, deactivation, desensitization, and recovery kinetics for the six isoforms using rapid-application recordings from excised macropatches. We found unique characteristics associated with each α subunit subtype. These properties would be expected to influence the post-synaptic response to GABA, creating functional diversity among neurons expressing different α subunits.

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“…Mammalian brain GABA A Rs are pentameric proteins composed of combinations of various subunit classes and isoforms (␣ 1-6 , ␤ 1Ϫ3 , ␥ 1Ϫ3 , ␦, ⑀, and ) and known splice variants (i.e., ␥ 2 long and ␥ 2 short forms) (for review, see Barnard et al, 1998;Mehta and Ticku, 1999;Whiting et al, 1999). The most common GABA A R subunit combination found in the brain contains two ␣ subunits, two ␤ subunits, and one ␥ subunit (Im et al, 1995;Chang et al, 1996;Li and De Blas, 1997;Jechlinger et al, 1998;Farrar et al, 1999), although combinations of two ␣, one ␤, and two ␥ subunits also occur in the brain (Backus et al, 1993;Khan et al, 1994aKhan et al, ,b, 1996.…”

Section: Individual Hippocampal Pyramidal Cells and Interneurons In Cmentioning

confidence: 99%

GABAergic Innervation Organizes Synaptic and Extrasynaptic GABA_AReceptor Clustering in Cultured Hippocampal Neurons

2002

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We have studied the effects of GABAergic innervation on the clustering of GABA A receptors (GABA A Rs) in cultured hippocampal neurons. In the absence of GABAergic innervation, pyramidal cells form small (0.36 Ϯ 0.01 m diameter) GABA A R clusters at their surface in the dendrites and soma. When receiving GABAergic innervation from glutamic acid decarboxylase-containing interneurons, pyramidal cells form large (1.62 Ϯ 0.08 m breadth) GABA A R clusters at GABAergic synapses. This is accompanied by a disappearance of the small GABA A R clusters in the local area surrounding each GABAergic synapse. Although the large synaptic GABA A R clusters of any neuron contained all GABA A R subunits and isoforms expressed by that neuron, the small clusters not localized at GABAergic synapses showed significant heterogeneity in subunit and isoform composition. Another difference between large GABAergic and small non-GABAergic GABA A R clusters was that a significant proportion of the latter was juxtaposed to postsynaptic markers of glutamatergic synapses such as PSD-95 and AMPA receptor GluR1 subunit. The densities of both the glutamate receptor-associated and non-associated small GABA A R clusters were decreased in areas surrounding GABAergic synapses. However, no effect on the density or distribution of glutamate receptor clusters was observed. The results suggest that there are local signals generated at GABAergic synapses that induce both assembly of large synaptic GABA A R clusters at the synapse and disappearance of the small GABA A R clusters in the surrounding area. In the absence of GABAergic innervation, weaker GABA A R-clustering signals, generated at glutamatergic synapses, induce the formation of small postsynaptic GABA A R clusters that remain juxtaposed to glutamate receptors at glutamatergic synapses.

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Molecular and Functional Diversity of the Expanding GABA‐A Receptor Gene Family

Cited by 317 publications

References 44 publications

Ionotropic GABA receptor expression in the lung during development

Ionotropic GABA receptor expression in the lung during development

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

GABAergic Innervation Organizes Synaptic and Extrasynaptic GABA_AReceptor Clustering in Cultured Hippocampal Neurons

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Molecular and Functional Diversity of the Expanding GABA‐A Receptor Gene Family

Cited by 317 publications

References 44 publications

Ionotropic GABA receptor expression in the lung during development

Ionotropic GABA receptor expression in the lung during development

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

GABAergic Innervation Organizes Synaptic and Extrasynaptic GABAAReceptor Clustering in Cultured Hippocampal Neurons

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GABAergic Innervation Organizes Synaptic and Extrasynaptic GABA_AReceptor Clustering in Cultured Hippocampal Neurons