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J. Biol. Chem., Vol. 269, Issue 45, 27925-27931, Nov, 1994
M Tiberi and MG Caron
Dopamine D1A and D1B receptor subtypes belong to the superfamily of G
protein-coupled receptors. Both receptors are coupled to the activation of
adenylyl cyclase and exhibit distinct brain distribution. To identify
functional differences, binding and stimulation of adenylyl cyclase were
assessed in 293 cells expressing transiently either dopamine D1A or D1B
receptors. Membranes expressing D1B receptors displayed higher affinities
for agonists than those expressing D1A receptors, whereas antagonist
affinities were lower at the D1B than at the D1A receptor. Basal activity
of adenylyl cyclase in whole 293 cells expressing various levels of D1B
receptors was significantly higher than the basal activity measured in
cells expressing D1A receptors. Maximal activation of adenylyl cyclase
resulting from stimulation of the D1B receptor was less than that obtained
following agonist activation of the D1A receptor. In cells expressing D1B
receptors, agonists displayed an increased potency for stimulating adenylyl
cyclase in comparison with the potencies determined for the D1A receptor.
On the other hand, certain antagonists displayed "negative efficacy" at
both receptor subtypes but had a more profound inhibition on the
agonist-independent signaling activity of the D1B receptor. The properties
described here are reminiscent of those of constitutively active G
protein-coupled receptors obtained by site-directed mutations. Thus, the
D1B receptor may represent a naturally occurring receptor subtype with
properties akin to those of constitutively active G protein-coupled
receptors. The different anatomical distribution and biochemical properties
of these D1 receptors strengthen the functional distinctions between the
two subtypes and could account for the basis of heterogeneity within a
given class of neurotransmitter or hormone receptors. In addition, if these
properties are recapitulated in cells expressing the D1B receptors, they
may underlie important role in the regulation of physiological effects by
dopamine. Finally, these results raise the interesting possibility that
psychotropic antagonist drugs used in the management of certain brain
disorders may have their beneficial actions as negative efficacy compounds.
High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype
Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, North Carolina 27710.
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