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Vol. 52, Issue 6, 1150-1156, 1997
-Aminobutyric Acid Type A
Receptors
Departments of
Pharmacology and Biochemistry, Neuroscience Research
Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex CM20
2QR, England (S.A.T., K.S., R.M., K.A.W.) and
PharmaBiotec Research
Center, Departments of Biological Sciences and Medicinal Chemistry, The
Royal Danish School of Pharmacy, Universitetsparken, DK-2100
Copenhagen, Denmark (B.E., P.K-L.)
Using human 
-aminobutyric acid type A (GABAA) receptor
subunit combinations, expressed in cell lines and Xenopus
laevis oocytes, the pharmacology of a number of ligands
interacting directly with the GABA recognition site has been studied in
[3H]muscimol binding and electrophysiologically. The
binding affinity of GABAA agonist and antagonist ligands
showed small but statistically significant dependence on the subunit
composition of receptors that include 2 and different 
and 
subunits. The potency of antagonist ligands was largely independent of
receptor subunit composition, whereas the composition of receptors
expressed in oocytes strongly influenced the EC50 value of
agonists. An apparent reciprocal correlation between subunits favoring
agonist binding and antagonist binding, respectively, was observed.
Whereas antagonists showed comparable potencies in binding and
functional studies, the potency of agonists in binding studies was
generally two to three orders of magnitude higher than the agonist
potencies measured electrophysiologically.
5-(4-Piperidyl)isothiazol-3-ol, which behaves as a low efficacy partial
agonist at GABAA receptors in cultured cortical neurons,
showed no efficacy in oocytes, but produced pure antagonist effects
with a binding/functional affinity ratio between those observed for the
agonists and antagonists. It is concluded that the GABAA
receptor mechanisms transducing binding into physiological response,
but not the binding per se, is dependent on the receptor
subunit composition.
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