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Abstract
BackgroundGamma-aminobutyric acid type B (GABAB) receptors decrease neural activity through G protein signaling. There are two subunits, GABAB1 and GABAB2. Alternative splicing provides GABAB1 with structural and functional diversity. cDNA microarrays showed strong signals from human brain RNA using GABAB1 intron 4 region probes. Therefore, we predicted the existence of novel splice variants.Methodology/Principal FindingsBased on the probe sequence analysis, we proposed two possible splice variants, GABAB1j and GABAB1k. The existence of human GABAB1j was verified by quantitative real-time PCR, and mouse GABAB1j was found from a microarray probe set based on human GABAB1j sequence. GABAB1j open reading frames (ORF) and expression patterns are not conserved across species, and they do not have any important functional domains except sushi domains. Thus, we focused on another possible splice variant, GABAB1k. After obtaining PCR evidence for GABAB1k existence from human, mouse, and rat, it was cloned from human and mouse by PCR along with three additional isoforms, GABAB1l, GABAB1m, and GABAB1n. Their expression levels by quantitative real-time PCR are relatively low in brain although they may be expressed in specific cell types. GABAB1l and GABAB1m inhibit GABAB receptor-induced G protein-activated inwardly rectifying K+ channel (GIRK) currents at Xenopus oocyte two-electrode voltage clamp system.Conclusions/SignificanceThis study supports previous suggestions that intron 4 of GABAB1 gene is a frequent splicing spot across species. Like GABAB1e, GABAB1l and GABAB1m do not have transmembrane domains but have a dimerization motif. So, they also could be secreted and bind GABAB2 dominantly instead of GABAB1a. However, only GABAB1l and GABAB1m are N- and C-terminal truncated splicing variants and impair receptor function. This suggests that the intron 4 containing N-terminal truncation is necessary for the inhibitory action of the new splice variants.
Highlights
The Gamma-aminobutyric acid type B (GABAB) receptor is a metabotropic receptor that is highly expressed in brain and weakly expressed in heart, small intestine, uterus and other tissues [1]
The functional receptor is a heterooligomer of GABAB1 and GABAB2 subunits, where the intracellular domain of GABAB1 dimerizes with GABAB2
Previous studies cloned GABAB1g, i, and j from rat, all of which have a portion of intron 4 [6,7,13]
Summary
The GABAB receptor is a metabotropic receptor that is highly expressed in brain and weakly expressed in heart, small intestine, uterus and other tissues [1]. The functional receptor is a heterooligomer of GABAB1 and GABAB2 subunits, where the intracellular domain of GABAB1 dimerizes with GABAB2. GABA binds to the extracellular domain of GABAB1 and transfers signals through G proteins. The GABAB receptor decreases the activity of AC and decreases neurotransmitter release by inhibiting Ca2+ influx through presynaptic Ca2+ channels. At postsynaptic neurons, it activates K+ channels, and an outward K+ current induces hyperpolarization preventing Na+ channel opening and action potential firing [2]. Gamma-aminobutyric acid type B (GABAB) receptors decrease neural activity through G protein signaling. Alternative splicing provides GABAB1 with structural and functional diversity. CDNA microarrays showed strong signals from human brain RNA using GABAB1 intron 4 region probes.
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