Four Amino Acids in the α Subunits Determine the γ-Aminobutyric Acid Sensitivities of GABAA Receptor Subtypes

Böhme, Ingo; Rabe, Holger; Lüddens, Hartmut

doi:10.1074/jbc.m405653200

Cited by 49 publications

(39 citation statements)

References 30 publications

(29 reference statements)

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“…Averaged hill numbers were not significantly different (p > 0.05) among the receptor isoforms and ranged from 1.04 ± 0.15 (α6) to 1.48 ± 0.12 (α1). The relative relationship of α6 < α4=α5 < α1=α2 < α3 is generally consistent with previously reported values using a variety of expression systems and subunit combinations (Dučićet al, 1995;Böhme et al, 2004).…”

Section: Whole-cell Gaba Sensitivitysupporting

confidence: 91%

“…A variety of heterogeneous sites within the extracellular Nterminal domain of α subunits have been reported to influence GABA sensitivity (Böhme et al, 2004;Drafts and Fisher, 2004) but few studies have examined the structural basis for differences in macroscopic kinetics. It is perhaps not surprising that complex interactions among different regions of the subunits appear to control deactivation and desensitization kinetics (Bianchi et al, 2001(Bianchi et al, , 2002aBianchi and Macdonald 2002;Fisher, 2004b).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Whole-cell Gaba Sensitivitysupporting

confidence: 91%

Section: Discussionmentioning

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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“…Sitedirected mutagenesis and molecular modeling have delineated the agonist binding site as formed by a series of ␤-sheet and loop motifs from ␣ and ␤ subunits, with several critical amino acid residues mediating molecular interactions between the receptor and agonist (Sigel et al, 1992;Wagner and Czajkowski, 2001;Wagner et al, 2004). Because the amino acid sequence is variable among isoforms, switching a single subunit (i.e., ␣1 to ␣3) can alter the identity of the key residues within the binding site (Bohme et al, 2004). This could produce changes in binding and unbinding kinetics by altering the physical shape of the binding pocket or through perturbation of molecular forces (i.e., electrostatic interactions) between the receptor and GABA.…”

Section: Discussionmentioning

confidence: 99%

GABA Affinity Shapes IPSCs in Thalamic Nuclei

Schofield¹,

Huguenard²

2007

J. Neurosci.

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Precise neural inhibition in thalamocortical circuits is required for the generation of sleep spindles and suppression of hypersynchrony associated with epileptiform activity. Accordingly, the time course of GABA A receptor-mediated IPSC events is an important parameter influencing the strength of inhibitory signaling. In the thalamus, two distinct types of IPSC kinetics are observed: thalamocortical relay neurons in the ventrobasal nucleus (VB) exhibit a fast decaying IPSC, whereas neurons in the adjacent reticular nucleus (RTN) display a long-lasting, slowly decaying IPSC. Here, we used patch-clamp electrophysiology and computational modeling to elucidate the basis for IPSC kinetic heterogeneity in the thalamus. Rapid application of GABA to excised membrane patches revealed that decay kinetics were attributable to intrinsic differences in GABA A receptor deactivation. Examination of desensitization and gating properties revealed these to be similar in VB and RTN, with the notable lack of fast and long-lasting desensitized states in both cell types. Computational simulations demonstrate that slow GABA binding and unbinding rates could reproduce the characteristic long-lasting IPSCs in RTN cells. These results indicate that within thalamic circuits, a powerful diversity of inhibitory function can result from simple differences in underlying GABA A receptor affinity.

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“…However, if GABA itself promotes the expression of KCC2 is still under debate (Ganguly et al 2001;Ludwig et al 2003;Titz et al 2003). Further, the a subunits are critical elements in determining the nature of the GABA A receptor response to GABA (Böhme et al 2004). The a3 mRNA (Gabra-3) is present at high levels in several forebrain regions at birth with a major decline after post-natal day 12 (P12), when the expression of a1 is going up (Laurie et al 1992).…”

Section: Editing Of the I/m Site Is Developmentally Regulatedmentioning

confidence: 99%

Editing modifies the GABAA receptor subunit 3

Ohlson¹,

Pedersen²,

Haussler³

et al. 2007

RNA

185

175

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Adenosine to inosine (A-to-I) pre-mRNA editing by the ADAR enzyme family has the potential to increase the variety of the proteome. This editing by adenosine deamination is essential in mammals for a functional brain. To detect novel substrates for A-to-I editing we have used an experimental method to find selectively edited sites and combined it with bioinformatic techniques that find stem-loop structures suitable for editing. We present here the first verified editing candidate detected by this screening procedure. We show that Gabra-3, which codes for the a3 subunit of the GABA A receptor, is a substrate for editing by both ADAR1 and ADAR2. Editing of the Gabra-3 mRNA recodes an isoleucine to a methionine. The extent of editing is low at birth but increases with age, reaching close to 100% in the adult brain. We therefore propose that editing of the Gabra-3 mRNA is important for normal brain development.

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Four Amino Acids in the α Subunits Determine the γ-Aminobutyric Acid Sensitivities of GABAA Receptor Subtypes

Cited by 49 publications

References 30 publications

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

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

GABA Affinity Shapes IPSCs in Thalamic Nuclei

Editing modifies the GABAA receptor subunit 3

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