Science

In Pursuit of the Endothelial Atypical Cannabinoid Receptor

Loren DeVito, PhD
Written by Loren DeVito, PhD

Are we there yet?

Before the green rush began, the only people using cannabis legally in the US were those prescribed it medically.And cannabis was commonly used for glaucoma – prompting images of “stoner” stereotypes to be replaced with grandmothers taking their eye medication. But how did cannabis help grandma keep her sight?

Glaucoma refers to a group of eye conditions,which cause an increase in pressure within the eye, leading to optic nerve damage and eventually blindness. Early studies in the 1970s showed that cannabis was effective in reducing intraocular pressure (IOP). While this effect has been attributed to the role of cannabinoid 1 (CB1) receptors within the eye, cannabinoids also cause vasodilation, or widening of blood vessels.1Since high blood pressure has been linked to IOP levels, cannabinoids may also prevent damage from glaucoma through their effects on the vascular system.2

Endothelial cells line the interior cavity of all blood vessels and play an important role in regulating blood flow throughout the body. These cells release a substance called endothelin-1 that regulates muscular tone within the blood vessels, causing them to constrict, which increases blood pressure. And while endocannabinoids like anandamide and synthetic cannabinoids like SR141716 cause vasodilation, studies have shown that this mode of action does not occur at the known CB1orCB2 receptors.3 So, then,what receptor is responsible forthis effect? And is it related to endothelial cells?

In 1999, researchers reported cannabinoid-induced vasodilation that occurred within the endothelium independent of CB1 and CB2 receptors.4Researchers began to call this receptor the “non-CB1/non-CB2 endothelial cannabinoid receptor,” or the “endothelial atypical cannabinoid receptor”. Just as with GPR55, the potential third cannabinoid receptor that may play a specific role in promoting cell cancer growth, there is a world of other receptors being explored that may explain some off-target effects of cannabinoids.

With the initial discovery of GPR55 (or the potential CB3 receptor), scientists thought it might be responsible for the endothelial-mediated vasodilation. However, a study that looked at the effect of cannabidiol on blood pressure in pre-clinical models lacking the GPR55 receptor found that there was no difference in vasodilation, meaning that GPR55 was not responsible for these effects.5

Further studies showed that vasodilation in human pulmonary arteries was indeed mediated by an “alleged” endothelial cannabinoid receptor.6 Other reports have referred to this receptor as CB4 (or eCB).7,8

While there is now considerable evidence indicating that vasodilation from cannabinoids occurs independently of CB1 and CB2, many unanswered questions remain.9First, the molecular structure of the eCB receptor remains unresolved. Second, most of the data we have comes from in vitro preparations (cells in petri dishes), making extrapolating its function within a living system difficult. Finally, there may be several other novel cannabinoid receptors that are contributing to this and other,incompletely described cannabinoid effects. So, it seems the scientific jury is out on definitively labeling this receptor “CB4” – at least for now.

By reaching far and wide beyond what’s known in the cannabinoid receptor world, it should be possible to develop receptor-specific, cannabinoid-based treatments for high blood pressure and other cardiovascular diseases. And we will get there, one study at a time.

References

  1. Tomida, R.G., Pertwee, A., Azuara-Blanco, I., et al.,“Cannabinoids and Glaucoma”,Br J Ophthalmol, 2004, Volume 88.

(impact factor: 3.806; cited by 126)

2.He, Z., Vingrys, A.J., Armitage , J.A., et al., “The role of blood pressure in glaucoma”,Clinical and Experimental Optometry, 2011, Volume 94.

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3.Begg, M., et al., “Evidence for Novel Cannabinoid Receptors”,Pharmacology & Therapeutics, 2005, Volume 106.

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  1. Jarai, Z, et al. “Cannabinoid-induced Mesenteric Vasodilation through an Endothelial Site Distinct from CB1 or CB2 Receptors”,PNAS, 1999, Volume 96.

(impact factor: 9.661; cited by 628)

  1. Johns, D.G., et al.,“The Novel Endocannabinoid Receptor GPR55 is Activated by Atypical Cannabinoids but Does Not Mediate Their Vasodilator Effects”,British Journal of Pharmacology, 2007, Volume 152.

(impact factor: 5.259; cited by 209)

  1. Kozlowska, H., et al.,“Virodhamine Relaxes the Human Pulmonary Artery through the Endothelial Cannabinoid Receptor and Indirectly through a COX Product”,British Journal of Pharmacology, 2008, Volume 155.

(impact factor: 5.259; cited by 32)

  1. Onaivi, E.S., et al. “Endocannabinoid Receptor Genetics and Marijuana Use”, In Endocannabinoids. The Brain and Body’s Endocannabinoids and Beyond. Eds. Onaivi. E.S., Sugiura, T., Di Marzo, V, 2006, CRC Press, Boca Raton, FL.

(impact factor: N/A; cited by 8)

  1. Iqbal, O. “Endocannabinoid System and Pathophysiology of Adipogenesis: Current Management of Obesity”,Personalized Medicine, 2007, Volume 4.

(impact factor: 1.010; cited by 6)

  1. Bondarenko, A.I., “Endothelial Atypical Cannabinoid Receptor: Do We Have Enough Evidence?”, British Journal of Pharmacology, 2014, Volume 171.

(impact factor: 5.259; cited by 15)

About the author

Loren DeVito, PhD

Loren DeVito, PhD

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