CB1 Signaling Research Articles

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.

CB1 and CB2 receptor-mediated signalling: a focus on endocannabinoids

The discovery that the major psychoactive component of marijuana activated two G-protein coupled receptors prompted the search for the endogenous cannabinoid ligands now termed endocannabinoids. To date three putative ligands have been isolated, all consisting of arachidonic acid linked to a polar head group. Both synthetic and endogenous cannabinoids have been the focus of extensive study over the past few years. The signalling events produced by endocannabinoids as compared with Δ9 -THC and synthetic cannabinoids contain many similarities. However, as research focuses more on endogenous ligands the divergence between these classes of compounds grows. This review focuses upon the developments in endocannabinoid signal transduction from receptor-mediated activation of common G-protein linked effector pathways through downstream regulation of gene transcription.

CB1 cannabinoid receptor expression in brain regions associated with zebra finch song control

Cannabinoids have been used for millennia through various preparations of Cannabis sativa. Despite this long history of use, the physiological significance of cannabinoid signaling in the vertebrate CNS is not well understood. High CB1 cannabinoid receptor densities in mammalian telencephalon and the results of behavioral studies suggest that cannabinoids play a role in cognitive function, learning, and memory. Since a network of discrete brain regions in zebra finch telencephalon controls song learning, we hypothesized that cannabinoid signaling may be relevant to songbird vocal development and behavior. Radioligand binding experiments using the cannabinoid agonist [ 3 H ]CP-55940 allowed identification of a dense population of high-affinity cannabinoid binding sites in zebra finch neuronal membranes. Northern blotting and RT–PCR experiments demonstrated expression of a predominant zebra finch CB1 mRNA of ∼5.5 kb. Expression of this CB1 mRNA appears to change over the course of vocal development within the caudal telencephalon. As zebra finch caudal telencephalon contains the higher vocal center (HVC) and the robust nucleus of the archistriatum (RA), regions involved in song learning and production, we further investigated CB1 expression in these areas using in situ hybridization. In situ hybridization revealed that CB1 mRNA is expressed at high levels within both HVC and RA. Overall, these data demonstrate the presence of CB1 signaling systems within songbird telencephalon, notably within regions known to be involved in song learning and production. High-level CB1 expression in song regions suggests a potential role for cannabinoid signaling in zebra finch vocal development.