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Vol. 57, Issue 3, 419-426, March 2000
-Aminobutyric
Acid (GABA) Binding at GABAB Receptors: Involvement of
Serine 269 of the GABABR1 Subunit
Centre Institut National de la Santé et de la Recherche
Médicale-Centre National de la Recherche Scientifique de
Pharmacologie-Endocrinologie, UPR 9023-Centre National de la Recherche
Scientifique, Montpellier, France (T.G., L.P., C.J., I.B., J.-P.P.);
and TA Nervous system, Novartis Pharma AG, Basel, Switzerland (S.U.,
J.M., B.M., J.H., W.F., B.B., K.K.).
The 
-aminobutyric acid (GABA) receptor type B (GABABR)
is constituted of at least two homologous proteins, GABABR1
and GABABR2. These proteins share sequence and structural
similarity with metabotropic glutamate and Ca2+-sensing
receptors, both of which are sensitive to Ca2+. Using rat
brain membranes, we report here that the affinity of GABA and
3-aminopropylphosphinic acid for the GABABR receptor is
decreased by a factor >10 in the absence of Ca2+. Such a
large effect of Ca2+ is not observed with baclofen or the
antagonists CGP64213 and CGP56999A. In contrast to baclofen, the
potency of GABA in stimulating GTPS binding in rat brain membranes
is also decreased by a factor >10 upon Ca2+ removal. The
potency for Ca2+ in regulating GABA affinity was 37 µM.
In cells expressing GABABR1, the potency of GABA, but not
of baclofen, in displacing bound 125I-CGP64213 was
similarly decreased in the absence of Ca2+. To identify
residues that are responsible for the Ca2+ effect, the
pharmacological profile and the Ca2+ sensitivity of a
series of GABABR1 mutants were examined. The mutation of
Ser269 into Ala was found to decrease the affinity of GABA, but not of
baclofen, and the GABA affinity was found not to be affected upon
Ca2+ removal. Finally, the effect of Ca2+ on
the GABAB receptor function is no longer observed in cells coexpressing this GABABR1-S269A mutant and the wild-type
GABABR2. Taken together, these results show that Ser269,
which is conserved in the GABABR1 protein from
Caenorhabditis elegans to mammals, is critical for the
Ca2+-effect on the heteromeric GABAB receptor.
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