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. 2007 Nov;152(5):825-31.
doi: 10.1038/sj.bjp.0707419. Epub 2007 Aug 20.

The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects

D G Johns  1 , D J Behm, D J Walker, Z Ao, E M Shapland, D A Daniels, M Riddick, S Dowell, P C Staton, P Green, U Shabon, W Bao, N Aiyar, T-L Yue, A J Brown, A D Morrison, S A Douglas
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The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects

D G Johns et al. Br J Pharmacol. 2007 Nov.

Abstract

Background and purpose: Atypical cannabinoids are thought to cause vasodilatation through an as-yet unidentified 'CBx' receptor. Recent reports suggest GPR55 is an atypical cannabinoid receptor, making it a candidate for the vasodilator 'CBx' receptor. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents.

Experimental approach: Human recombinant GPR55 was expressed in HEK293T cells and specific GTPgammaS activity was monitored as an index of receptor activation. In GPR55-deficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myography were used to determine GPR55 dependence of atypical cannabinoid-induced haemodynamic and vasodilator responses.

Key results: Atypical cannabinoids O-1602 and abnormal cannabidiol both stimulated GPR55-dependent GTPgammaS activity (EC50 approximately 2 nM), whereas the CB1 and CB2-selective agonist WIN 55,212-2 showed no effect in GPR55-expressing HEK293T cell membranes. Baseline mean arterial pressure and heart rate were not different between WT and GPR55 KO mice. The blood pressure-lowering response to abnormal cannabidiol was not different between WT and KO mice (WT 20+/-2%, KO 26+/-5% change from baseline), nor was the vasodilator response to abnormal cannabidiol in isolated mesenteric arteries (IC50 approximately 3 micro M for WT and KO). The abnormal cannabidiol vasodilator response was antagonized equivalently by O-1918 in both strains.

Conclusions: These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents.

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Figures

Figure 1
Figure 1
Atypical cannabinoids stimulate GPR55 GTPγS activity. Membranes from HEK293T cells expressing human recombinant GPR55 were utilized for GTPγS activity as described in Materials and methods. (a) Abnormal cannabidiol and (b) the synthetic abnormal cannabidiol analogue O-1602 stimulate GTPγS activity with similar potency. Data points represent means±s.e.mean of n=3 experiments.
Figure 2
Figure 2
Abnormal cannabidiol administration (30 mg kg−1 i.v. bolus) results in similar blood pressure-lowering effect in GPR55 KO compared to WT. (a) Mean arterial pressure and (b) heart rate from baseline values are shown. Data are presented as mean±s.e.mean (n=8). GPR55 KO, mice homozygous for the GPR55 mutation; WT, wild-type littermate controls for GPR55 KO mice.
Figure 3
Figure 3
Vascular reactivity in unaltered in GPR55 KO mice compared to WT. (a) Contractile response to phenylephrine, normalized to contraction to 60 mM KCl challenge, (b) vasodilation to abnormal cannabidiol, (c) vasodilation to O-1602. Each data point represents mean±s.e.mean (n=5). GPR55 KO, mice homozygous for the GPR55 mutation; WT, wild-type littermate controls for GPR55 KO mice.
Figure 4
Figure 4
Antagonism of abnormal cannabidiol-induced vasodilatation by O-1918 is not different between GPR55 KO and WT mice. Preincubation of mesenteric resistance arteries with O-1918 (30 μM) caused similar shifts in the concentration–response curve to abnormal cannabidiol in (a) WT and (b) KO vessels. Data are presented as mean±s.e.mean (n=4). GPR55 KO, mice homozygous for the GPR55 mutation; WT, wild-type littermate controls for GPR55 KO mice.
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