B GABAb Receptors

GABAB receptors are located both pre- and postsy-naptically and they appear to be largely extrasynaptic. GABAB receptors are G protein-coupled receptors that interact with a number of proteins on K + and Ca2+ channels as well as with adenylate cyclase. They belong to the class C metabotropic receptor family, which includes the metabotropic glutamate receptors. The GABAB receptor has only recently been cloned, and our understanding of this receptor is therefore more limited than that of the GABAa receptor.

GABAB activation is inhibitory both pre- and postsynaptically. Presynaptic GABAB receptor activation causes Ca2 + channels to close, which decreases Ca2 + conductance. Decreased Ca2+ conductance at the nerve terminal reduces exocytotic release of

1. Receptor Topology

GABAB receptors are unique within the metabotropic receptor family because they exist as heterodimers. Functional GABAB receptors require the GBR1 and GBR2 subunits in order to be expressed at the cell surface, to bind ligand, and to mediate action. Both GBR1 and GBR2 have seven transmembrane domains, with extracellular amino termini and intracel-lular carboxy termini (Fig. 6). The amino terminus of GBR1 provides a GABA binding site, whereas the intracellular loops and carboxy terminus participate in G protein binding. GBR2 does not appear to interact with GABA. GBR1 and GBR2 interact via the carboxy domain, and this interaction is necessary in order to direct GBR1 expression to the cell surface.

Figure 6 GABAB receptor subunit and complex topology. The GABAB receptor is composed of two similar subunits, each with seven transmembrane domains, extracellular amino termini, and intracellular carboxy termini. The putative GABA binding site, denoted by an asterisk, is on the amino terminus of GABABR1. The subunits interact via their carboxy domains.

Figure 6 GABAB receptor subunit and complex topology. The GABAB receptor is composed of two similar subunits, each with seven transmembrane domains, extracellular amino termini, and intracellular carboxy termini. The putative GABA binding site, denoted by an asterisk, is on the amino terminus of GABABR1. The subunits interact via their carboxy domains.

2. Subunit Composition

There are at least four isoforms of GBR1, GBR1a-GBRld, which range in size from approximately 100 to 130 kDa. The GBRla isoform may be more prevalent at presynaptic sites, whereas the GBR1b isoform is predominantly found postsynaptically. GBR1 and GBR2 share 35% homology with each other but have little homology with other metabo-tropic receptors.

GAT2 and GAT3 are also found in peripheral tissues, including the liver and kidney.

Na + - and Cl"-dependent transporters rely on the ionic gradients across the membrane. GABA transport is an electrogenic process that cotransports approximately two Na+ ions and one Cl" ion with each GABA molecule. Since the ionic gradients normally favor inward transport, GABA usually is transported into the cell. Under conditions of high intracellular Na+ or membrane depolarization, however, GABA can be released through the transporter.

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