Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk?
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.
Kearn
Christopher S
CS
Department of Anesthesiology, University of Washington, Seattle, USA.
Blake-Palmer
Katherine
K
Daniel
Emma
E
Mackie
Ken
K
Glass
Michelle
M
D002460:Cell Line; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019257:Quinpirole / Q000378:metabolism / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000096:biosynthesis* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis* / Q000235:genetics
D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D019257:Quinpirole