Calcium sensing properties of the GABA(B) receptor.
The GABA(B) receptor has been shown to consist of a heterodimer of two related 7-transmembrane receptors GABAB-R1 and GABA(B)-R2. These receptors share close homology to the Ca2+-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 Ca2+ sensing properties. Ca2+ (0.001-1 mM) potentiated the GABA stimulation of [35S]GTPgammaS binding in membranes prepared from CHO cells stably expressing the GABA(B)-R1/R2 heterodimer. The GABA EC50 was reduced from 72 to 7.7 microM by addition of 1 mM Ca2+, with no change in the maximum response. A similar effect was observed in membranes from rat brain cortex. Ca2+ 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 Ca2+ 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 Ca2+-sensing receptor and some of the mGluR family, Ca2+ does not act as a ligand in its own right.
Wise
A
A
Receptor Systems, Molecular Pharmacology Unit, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, UK.
Green
A
A
Main
M J
MJ
Wilson
R
R
Fraser
N
N
Marshall
F H
FH
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000494:pharmacology* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D018755:GABA Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D008297:Male; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology
D018755:GABA Agonists; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D002118:Calcium