Abstract
The GABA B receptor has been shown to consist of a heterodimer of two related 7-transmembrane receptors GABA B-R1 and GABA B-R2. These receptors share close homology to the Ca 2+-sensing receptor and also to the metabotropic glutamate receptors, which have also been shown to respond to extracellular calcium. We show here that the GABA B receptor also has Ca 2+ sensing properties. Ca 2+ (0.001–1 mM) potentiated the GABA stimulation of [ 35S]GTPγS binding in membranes prepared from CHO cells stably expressing the GABA B-R1/R2 heterodimer. The GABA EC 50 was reduced from 72 to 7.7 μM by addition of 1 mM Ca 2+, with no change in the maximum response. A similar effect was observed in membranes from rat brain cortex. Ca 2+ also potentiated GABA inhibition of forskolin-stimulated cAMP levels in the CHO cells and enhanced coupling to GIRK K + channels in Xenopus oocytes. Other divalent cations were ineffective. The effects of Ca 2+ were found to be agonist dependent with baclofen having a reduced sensitivity compared to GABA. Calcium appears to act allosterically to enhance GABA responses at the GABA B receptor, however, unlike the Ca 2+-sensing receptor and some of the mGluR family, Ca 2+ does not act as a ligand in its own right.
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