PMID:15710746
| Citation |
Kearn, CS, Blake-Palmer, K, Daniel, E, Mackie, K and Glass, M (2005) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol. Pharmacol. 67:1697-704 |
|---|---|
| Abstract |
Dopamine and endogenous cannabinoids display complex interactions in the basal ganglia. One possible level of interaction is between CB1 cannabinoid and D2 dopamine receptors. Here, we demonstrate that a regulated association of CB1 and D2 receptors profoundly alters CB1 signaling. This provides the first evidence that CB1/D2 receptor complexes exist, are dynamic, and are agonist-regulated with highest complex levels detected when both receptors are stimulated with subsaturating concentrations of agonist. The consequence of this interaction is a differential preference for signaling through a "nonpreferred" G protein. In this case, D2 receptor activation, simultaneously with CB1 receptor stimulation, results in the receptor complex coupling to G alpha s protein in preference to the expected G alpha i/o proteins. The result of this interaction is an increase in the second messenger cAMP, reversing an initial synergistic inhibition of adenylyl cyclase activity seen at subthreshold concentrations of cannabinoid agonist. Additionally, a pertussis toxin insensitive component in the activation of extracellular signal-regulated kinase (ERK) 1/2 kinases by the cannabinoid agonist CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] is revealed in cells stably expressing both CB1 and D2 receptors. Thus, concurrent receptor stimulation promotes a heterooligomeric receptor complex and an apparent shift of CB1 signaling from a pertussis toxin-sensitive inhibition to a partly pertussis toxin-insensitive stimulation of adenylyl cyclase and ERK 1/2 phosphorylation. |
| Links |
PubMed Online version:10.1124/mol.104.006882 |
| Keywords |
Cell Line; Dimerization; Dose-Response Relationship, Drug; Humans; Quinpirole/metabolism; Quinpirole/pharmacology; Receptor Cross-Talk/drug effects; Receptor Cross-Talk/physiology; Receptor, Cannabinoid, CB1/biosynthesis; Receptor, Cannabinoid, CB1/genetics; Receptors, Dopamine D2/biosynthesis; Receptors, Dopamine D2/genetics |
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