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Fig. 2. Representation of the various variants of GABAB(1). The two main isoforms are GABAB(1a) and GABAB(1b) originally cloned by Kaupman et al. (1997). Other variants include GABA(1c_a) and GABAB(ic_b), which are rat variants with an additional insertion spliced into the second extracellular loop (SI). GABAB(1c) is a human variant without the first CCP domain. GABAB(1c) would be soluble form if produced in vivo. Other abbreviations: CC coiled-coil domain and RSRR C-ter-minal endoplasmic reticulum (ER) retention signal. (Adapted from Bettler et al., 2004, used with permission.)

Fig. 2. Representation of the various variants of GABAB(1). The two main isoforms are GABAB(1a) and GABAB(1b) originally cloned by Kaupman et al. (1997). Other variants include GABA(1c_a) and GABAB(ic_b), which are rat variants with an additional insertion spliced into the second extracellular loop (SI). GABAB(1c) is a human variant without the first CCP domain. GABAB(1c) would be soluble form if produced in vivo. Other abbreviations: CC coiled-coil domain and RSRR C-ter-minal endoplasmic reticulum (ER) retention signal. (Adapted from Bettler et al., 2004, used with permission.)

the human GABAB(1c) variant has been reported to be up-regulated Calver et al. (2000) and Blein et al. (2004) have examined the structure of the two sushi or complement control protein (CCP) domains in GABAB(1a). They showed that the two sushi/CCP modules differ strikingly in structure with the second CCP module (CCP2) having a structure very similar to the CCP module in other proteins whilst CCP1 in GABAB(1a) has a more disordered structure although like CCP2 it could bind the extracellular protein, fibulin-2 (Blein et al., 2004).

In contrast to the variety of transcripts found for the GABAB(1) subunit, the GABAB(2) transcripts reported in man may be artefacts as consideration of the genomic sequence does not indicate the presence of appropriate splice sites to generate these alternative transcripts and GABAB(2) does not seem to occur in alternative forms (Martin et al., 2001). Regional distribution studies indicate that there are significant differences between the distribution of GABAB(1a) and GABAB(1b) mRNA and protein, that is the GABAB(1) subunits

GABAB(1a) with the sushi or CCP domains, and GABAB(1b) without the sushi domains, with variable amounts of 1a and 1b protein or being found in cerebral cortex hippocampus and brain stem (see for example Kaupmann et al., 1998b; Benke et al., 1999; Bischoff et al., 1999; Poorkhalkali et al., 2000; Princivalle et al., 2001). In these regions the 1b form is more prominent but in the striatum (Fig. 3) the 1a form (with the sushi domains) is more abundant. The significance of this difference is so far unclear but it may allow possible interactions of the NH2 terminal extracellular sequence with other extracellular/surface proteins (such as fibulin-2) on neighbouring striatal neurones or influence the subcellular localization of the receptor.

Surprisingly the two subunits 1a and 1b arise not from alternative splicing, but from the use of an alternative promoter where the short GABAB(1b) NH2 terminal arises from transcription within a GABAB(1a) intron resulting in extension of exon 6 at its 5' end (Pfaff et al., 1999; Martin et al., 2001). Of more interest with respect to the striatum is that the GABAB(2) mRNA is only poorly expressed in this region (Bischoff et al., 1999; Kuner et al., 1999; Margeta-Mitrovic et al., 1999; Martin et al., 1999; Clark et al., 2000) so it had been suggested that in this region the GABAB(1) protein might interact with another partner. However, in the GABAB(2) knockout described by Thuault et al. (2004) there was no evidence for functional GABAB(1) receptors on striatal neurones. This does not completely resolve the issue as the GABAB(2) knockout produced by Thuault et al. (2004) probably expressed a mutated GABAB(2) protein expression albeit without function, so that in contrast to the full GABAB(2) knockout described by Gassmann et al. (2004) the presence of the GABAB(2) mutated protein may have prevented the GABAB(1) receptor protein from trafficking to the surface on its own, or with another partner. However, what is clear is that the presence of the functional GABAB(2) protein is required for the established GABAB response in striatal neurones. For basal ganglia neuronal function it may be important that the GABAB(1) subunit interacts with the common GABAA receptor subunit g2S, which is highly expressed in the basal

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