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Identification of N-arachidonoyl dopamine as a highly biased ligand at cannabinoid CB1 receptors.


ABSTRACT:

Background and purpose

N-arachidonyl dopamine (NADA) has been identified as a putative endocannabinoid, but there is little information about which signalling pathways it activates. The purpose of this study was to identify the signalling pathways activated by NADA in vitro.

Experimental approach

Human or rat cannabinoid CB1 receptors were expressed in AtT20, CHO or HEK 293 cells. NADA displacement of radiolabelled cannabinoids, and CB1 receptor mediated activation of K channels or ERK phosphorylation, release of intracellular calcium ([Ca]i ) and modulation of adenylyl cyclase were measured in addition to NADA effects on CB1 receptor trafficking.

Key results

At concentrations up to 30??M, NADA failed to activate any signalling pathways via CB1 receptors, with the exception of mobilization of [Ca]i . The elevations of [Ca]i were insensitive to pertussis toxin, and reduced or abolished by blockers of Gq /11 -dependent processes including U73122, thapsigargin and a peptide antagonist of Gq /11 activation. Prolonged NADA incubation produced modest loss of cell surface CB1 receptors. The prototypical cannabinoid agonist CP55940 signalled as expected in all assays.

Conclusions and implications

NADA is an ineffective agonist at most canonical cannabinoid receptor signalling pathways, but did promote mobilization of [Ca]i via Gq -dependent processes and some CB1 receptor trafficking. This signalling profile is distinct from that of any known cannabinoid, and suggests that NADA may have a unique spectrum of effects in vivo. Our results also indicate that it may be possible to identify highly biased CB1 receptor ligands displaying a subset of the pharmacological or therapeutic effects usually attributed to CB1 ligands.

SUBMITTER: Redmond WJ 

PROVIDER: S-EPMC4813372 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Identification of N-arachidonoyl dopamine as a highly biased ligand at cannabinoid CB1 receptors.

Redmond William J WJ   Cawston Erin E EE   Grimsey Natasha L NL   Stuart Jordyn J   Edington Amelia R AR   Glass Michelle M   Connor Mark M  

British journal of pharmacology 20151117 1


<h4>Background and purpose</h4>N-arachidonyl dopamine (NADA) has been identified as a putative endocannabinoid, but there is little information about which signalling pathways it activates. The purpose of this study was to identify the signalling pathways activated by NADA in vitro.<h4>Experimental approach</h4>Human or rat cannabinoid CB1 receptors were expressed in AtT20, CHO or HEK 293 cells. NADA displacement of radiolabelled cannabinoids, and CB1 receptor mediated activation of K channels o  ...[more]

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