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Vol. 52, Issue 6, 1137-1149, 1997
Veterans Affairs Medical Center and Departments of Behavioral
Neuroscience (K.A.N.) and
Physiology and Pharmacology (L.B.K., K.A.N.),
Oregon Health Sciences University, Portland, Oregon 97201
Chimeric D1/D2 receptors were constructed to
identify structural determinants of drug affinity and efficacy. We
previously reported that chimeras that had D1 receptor
transmembrane domain VII together with amino-terminal sequence from the
D2 receptor were nonfunctional.
D2/D1 chimeras were constructed that contained D2 receptor sequence at the amino- and carboxyl-terminal
ends and D1 receptor sequence in the intervening region.
Chimeric receptors with D2 sequence from transmembrane
domain 7 to the carboxyl terminus together with D2 receptor
sequence from the amino terminus through transmembrane helix 4 (D2[1-4,7]) and 5 (D2[1-5,7]) bound
[3H]spiperone with high affinity, consistent with the
hypothesis that D2 receptor transmembrane domain I or II is
incompatible with D1 receptor transmembrane domain VII.
D2[1-4,7] and D2[1-5,7] had affinities
similar to D1 and D2 receptors for most
nonselective dopamine antagonists and had affinities for most of the
selective antagonists that were intermediate between those of the
parent receptors. D2[1-4,7] and D2[1-5,7]
mediated dopamine receptor agonist-induced stimulation and inhibition,
respectively, of cAMP accumulation. The more efficient coupling of
D2[1-5,7] to inhibition of cAMP accumulation, compared
with the coupling of D2[5-7] and D2[3-7],
supports the view that multiple D2 receptor cytoplasmic
domains acting in concert are necessary for receptor activation of
Gi. In contrast, D2[1-4,7], which contains
only one cytoplasmic loop (the third) from the D1 receptor,
is capable of activating Gs. D2[1-4,7] exhibited several characteristics of a constitutively active receptor, including enhanced basal (unliganded) stimulation of cAMP accumulation, high affinity for agonists even in the presence of GTP, and blunted agonist-stimulated cAMP accumulation. A number of dopamine receptor antagonists were inverse agonists at D2[1-4,7], inhibiting basal cAMP accumulation. Some of these drugs were also inverse agonists at the D1 receptor. Interestingly, several
antagonists also potentiated forskolin-stimulated cAMP accumulation via
D2[1-5,7] and via the D2 receptor, which
could reflect inverse agonist inhibition of native constitutive
activity of this receptor.
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