Relationships Between Ligand Affinities for the Cerebellar Cannabinoid Receptor CB1 and the Induction of GDP/GTP Exchange

Abstract

Abstract:The hypothesis of these studies is that ligand efficacy at the neuronal CB1 receptor is dependent on the ratio of ligand affinities for the active and inactive states of the receptor. Agonist efficacy was determined in rat cerebellar membranes using agonist-induced guanosine 5Ј-O-(3-[35 S]thiotriphosphate) binding; efficacy was variable among the CB1 agonists examined. Ligand affinities for the active and inactive state of the CB1 receptor were determined by competition with [ 3 H]CP55940 and [3 H]SR141716A in the presence of 5Ј-guanylylimidodiphosphate, respectively. All of the agonists investigated had a higher affinity for the active state than the inactive state. The fraction of CB1 receptors in the active state at a maximally effective concentration was calculated for each agonist and was found to correlate significantly with agonist efficacy. These studies demonstrate that the CB1 receptor of the cerebellum can assume an active conformation in the absence of agonist and that the variability in efficacy among CB1 receptor agonists can be explained by the relative affinities of these ligands for the CB1 receptor in the active and inactive states. Key Words: Anandamide -CP55940 -⌬ 9 -Tetrahydrocannabinol-HU210 -Inverse agonistMarijuana-N-Arachidonylethanolamine -SR141716A-WIN 55212-2.

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims

“…Recently, a nonhydrolyzable GTP analogue, [ 35 S]GTPgS, has been employed to asses the coupling efficacy of several neurotransmitter receptors and Gproteins in cortical membranes of human postmortem brain. 27 The results of the present study suggest greater CB 1 receptor-stimulated [ 35 31 This is borne out from direct comparison between the efficacy of cannabinoids and opiates in which opiates signaling was found to be 20-fold more efficient than cannabinoid signaling. 32 Therefore, it is speculated that the CB 1 receptor signaling functions as a subtle, fine-tuning mechanism for cells.…”

“…The high density of receptors makes the CB 1 receptor highly sensitive to agonists; however, the poor coupling efficiency ensures that overactivation of the system will not occur. 31 The consequence of elevated CB 1 receptor-mediated signaling in the pathophysiology of depression is not known. Abnormalities in cAMP signaling in depressive disorders have been reported.…”

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats

“…27 THC is a partial agonist with a lower affinity and efficacy relative to WIN, hence its ability to activate the CB 1 receptor will be influenced by the density and coupling efficiencies of these receptors in different brain regions. [28][29][30] We are not the first group to show effects on decision-making following THC that are not replicated by a synthetic CB 1 agonist: THC, but not WIN, increased HR choice in a task involving delay costs. 9,24 Perhaps the most parsimonious explanation for the discrepancy between the effects of these agonists relates to their ability to recruit differential signalling cascades.…”

Synergistic Interactions between Cannabinoids and Environmental Stress in the Activation of the Central Amygdala

“…The in vivo potency difference between THC and CP55940 in the activation of Fos expression within the CeA (less than 10-fold) is far less than that predicted by the differences in binding affinity for CB 1 receptors (about an 80-fold difference) (Hillard et al, 1995). THC has lower efficacy at CB 1 receptor activation compared to CP55940 (Kearn et al, 1999), which further suggests that in vivo differences between THC and CP55940 do not correlate with in vitro pharmacological properties. It is possible that the high affinity and efficacy of CP55940 result in robust receptor internalization and desensitization (Hsieh et al, 1999).…”