GABAB-receptor isoforms: Molecular architecture and distribution

doi:10.1016/S0024-3205(01)01018-9

Life Sciences

Volume 68, Issues 19–20, 6 April 2001, Pages 2297-2300

https://doi.org/10.1016/S0024-3205(01)01018-9 Get rights and content

Abstract

The slow component of GABAergic inhibition in the brain is mediated by the metabotropic GABA_B-receptors. Most if not all GABA_B-receptors are heterodimers of GABA_BR1 (GBR1) and GABA_BR2 (GBR2) proteins. Distinctive receptor isoforms are based on the presence of two GBR1 splice variants termed GBR1a and GBR1b. Both were found to be associated with GBR2 suggesting that the isoforms GBR1a/GBR2 and GBR1b/GBR2 represent the vast majority of GABA_B-receptors in the brain. The two isoforms differed strikingly in their pattern of expression on the regional, cellular and subcellular level. These results point to distinct funcional roles of the two receptor isoforms.

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Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the retina and affects myopic development. Electroacupuncture (EA) is widely utilized to treat myopia in clinical settings. However, there are few reports on whether EA affects the level of retinal GABA during myopic development. To study this issue, in the present study, we explored the changes of retinal GABA content and the expression of its receptor subtypes, and the effects of EA stimulation on them in a guinea pig model with lens-induced myopia (LIM). Our results showed that the content of GABA and the expression of GABA_A and GABA_C receptors of retina were up-regulated during the development of myopia, and this up-regulation was inhibited by applying EA to Hegu (LI4) and Taiyang (EX-HN5) acupoints. Moreover, these effects of EA show a positional specificity. While applying EA at a sham acupoint, no apparent change of myopic retinal GABA and its receptor subtypes was observed. Taken together, our findings suggest that LIM is effective to up-regulate the level of retinal GABA, GABA_A and GABA_C receptors in guinea pigs and the effect may be inhibited by EA stimulation at LI4 and EX-HN5 acupoints.
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It is well established that Gαo/i inhibits adenylyl cyclase while Gβγ gates G protein-activated inwardly rectifying K+ (GIRK/Kir3) channels (Betke, Wells, & Hamm, 2012; Luscher & Slesinger, 2010) and voltage-activated Ca2 + channels (Betke et al., 2012; Chalifoux & Carter, 2011b; Perez-Garci, Larkum, & Nevian, 2013; Tedford & Zamponi, 2006). GABABRs are expressed by the vast majority of neurons in the central nervous system (Mohler, Benke, & Fritschy, 2001). The two prevalent subunit isoforms GABAB1a and GABAB1b target GABABRs to pre- and postsynaptic sites, respectively (Biermann et al., 2010; Perez-Garci, Gassmann, Bettler, & Larkum, 2006; Shaban et al., 2006; Vigot et al., 2006).
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While the highest densities of the R1A variant were located in the substantia nigra, ventral tegmental area, periaqueductal gray, hippocampus and cortex, the R1B variant was more restricted in its distribution with higher concentrations in the thalamus, habenula and cerebellum (Bischoff et al., 1999). As expected, since the GABAB R2 variant is required for a functional GABAB receptor, the distribution of the R2 variant largely parallels that of the R1A and R1B (Mohler et al., 2001). Interestingly, many of the brain areas in the current study that exhibited the greatest degree of tolerance to the functional effects of baclofen (for example substantia nigra, hippocampus, thalamus and cerebellum) also contain the highest densities of GABAB receptors (Bischoff et al., 1999), while regions with more moderate levels of GABAB receptors, such as the caudate putamen, exhibited a lesser degree of tolerance.
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Citation Excerpt :
In addition to reduced GABAB(1) receptor mRNA expression, a failure of these receptors to localise to distal dendrites of WAG/Rij neocortical pyramidal cells and a reduction in paired pulse depression in WAG/Rij rats were also observed, implicating relevant functional consequences associated with these expression changes. It should be noted that GABAB(1a,2) and GABAB(1b,2) are the major GABAB receptors in the brain [64]. Several ion channels are highly expressed in thalamocortical brain regions and emerging literature has implicated these in SWD genesis.
The idiopathic generalized epilepsies (IGEs), constituting approximately a quarter of all epilepsy cases, are presumed to arise primarily from genetic abnormalities. A minority of cases have been identified to be caused by mutations in a single gene, but in the vast majority, mutations in multiple genes are presumed to contribute to the development of epilepsy. Two rat models of IGE with absence seizures, the Genetic Epilepsy Rats from Strasbourg (GAERS) and Wistar Albino Glaxo from Rijswijk (WAG/Rij), have proven valuable for translational research. These models closely mimic the behavioural, electrophysiological, and pharmacological aspects of the human condition, with the epilepsy phenotype for both likely to have polygenic determinants. Research in these models, using molecular and in vivo imaging approaches, has provided important insights into the pathophysiology of IGE. Molecular and imaging techniques have the potential to provide researchers with tangible biomarkers of disease progression and the effects of intervention, and also to provide fundamental information about the causation and epileptogenic processes associated with IGE. This review discusses the published literature concerning the molecular changes and morphometric abnormalities identified in these models, as well as their potential relevance for human IGE.

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Cloning and regulation g-protein coupled receptorGABAB-receptor isoforms: Molecular architecture and distribution

Abstract

Cloning and regulation g-protein coupled receptor
GABA_B-receptor isoforms: Molecular architecture and distribution