Abstract:
:There are now several examples of single G protein-coupled receptors to which binding of specific agonists causes differential effects on the associated signaling pathways. The dopamine D(2) receptor is of special importance because the selective activation of functional pathways has been shown both in vitro and in situ. For this reason, the present work characterized a series of rigid D(2) agonists in Chinese hamster ovary cells transfected with the human D(2L) receptor using three distinct functional endpoints: inhibition of cAMP synthesis, stimulation of mitogen-activated protein (MAP) kinase phosphorylation, and activation of G protein-coupled inwardly rectifying potassium channels (GIRKs). In this system, S-propylnorapomorphine (SNPA), R-propylnorapomorphine (RNPA), dihydrexidine (DHX), dinapsoline (DNS), and dinoxyline (DNX) all inhibited forskolin-stimulated adenylate cyclase activity to the same extent as the prototypical D(2) agonist quinpirole (QP). The rank order of potency was the following: RNPA > QP = DNX > SNPA > DHX = DNS. For MAP kinase phosphorylation, DHX, DNS, DNX, and RNPA had efficacy similar to QP, whereas SNPA was a partial agonist. The rank order of potency for MAP kinase phosphorylation was RNPA > QP = DNX > DHX > DNS = SNPA. DNX activated GIRK channels to the same extent as QP, whereas DHX and DNS were partial agonists, and RNPA and SNPA caused no appreciable activation. These findings indicate that DHX, DNS, RNPA, and SNPA have atypical functional properties at the hD(2L) receptor and display different patterns of functional selectivity. We hypothesize that this functional selectivity may be a result of ligand induction of specific conformations of the D(2L) receptor that activate only selected signaling pathways.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Gay EA,Urban JD,Nichols DE,Oxford GS,Mailman RBdoi
10.1124/mol.66.1.97keywords:
subject
Has Abstractpub_date
2004-07-01 00:00:00pages
97-105issue
1eissn
0026-895Xissn
1521-0111pii
66/1/97journal_volume
66pub_type
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