Cannabinoid receptors can link with other receptors and modify their function, opening a new avenue for understanding how cannabinoid exert their effects.

I previously showed how endocannabinoids like anandamide can directly interact with receptors outside the cannabinoid system. However, this alone does not explain the multitude of effects that cannabinoids have. There is another important way that cannabinoids can interact with other systems – this is through receptor dimerization.

This process is turning out to be so important for how cannabinoids work – including both for beneficial health effects as well as for undesired side effects. For example, a potential role of cannabinoid receptor dimers has been explored in:

  • Tolerance to pain-blocking effects of opiates
  • Depression and anxiety in chronic pain
  • Negative effects of cannabis on memory
  • Parkinson’s and Huntington’s Disease
  • Cancer cell metastasis

GPCR Dimerization

CB1 and CB2 belong to a class of receptors called G-protein coupled receptors (or GPCRs). These receptors were traditionally thought to function as independent units. Then it was discovered that two of the same GPCRs could come together in the cell membrane to form a receptor homodimer. The CB1 receptor homodimer was first characterized in a 2002 study, although the consequences of this remain unknown

The next discovery was even more surprising – different types of GPCRs could bind each other to form a receptor heterodimer (also called a heteromer for short). This opened up an exponential number of ways that a single receptor (for example, the cannabinoid CB1 receptor) could influence other neurotransmitter systems.

What can heterodimerization change about how the receptor functions? A lot of things:

  • Receptor signaling: Increasing or decreasing the signal generated from the receptor or even changing the signaling pathway activated by the receptor.
  • Ligand binding: Changing the affinity of a ligand for its receptor
  • Receptor Trafficking: Location of the receptor on the membrane or internalization of the receptor into the cell

I will highlight the effects of some key cannabinoid receptor dimers below:

Cannabinoid CB1 CB2  receptor dimerization heterodimers

CB1 & Opioid Receptors

The  μ opioid receptor (μOR) is activated by opiates such as morphine and is largely responsible for their pain-blocking effects.

Multiple studies have shown that CB1 and μOR form a heteromer with unique properties. Activation of either receptor allows signaling, but activation of both receptors in the heteromer causes a decrease in signaling. This heteromer may also be involved in developing tolerance to the pain-blocking effects of opiates.

The CB1 receptor is expressed in the same cortical neurons as another opioid receptor subtype – the δ opioid receptor (δOR). The δOR is able to reduce anxiety and depressive-like behavior. Low δOR activity may be responsible for anxiety and depression in people with chronic pain.

Many interactions have been demonstrated between CB1 and δOR – they tend to inhibit each others function. If the CB1 receptor is missing, then δOR activity is higher, and vice versa. So it was not much surprise when it was discovered that these receptors interact directly by forming a heteromer.

This heteromer was increased in the brains of rats with neuropathic pain, which may contribute to low δOR signaling and anxiety. However, low doses of a CB1 agonist were able to increase δOR activity through a conformation change of the dimer.

CB1 & Serotonin Receptors

The serotonin 2A (5-HT2A) receptor is one of the most fascinating in the brain. It is the receptor activated by hallucinogens such as LSD, psilocin, and mescaline. It also has roles in the effects of antidepressants and antipsychotics.

Both the CB1 and 5-HT2A receptors are co-expressed in the same neurons in the amygdala, cerebral cortex, and hippocampus, parts of the brain that regulate emotions, learning, and memory. An interaction between these receptors was long suspected since activation of CB1 by THC and other cannabinoids can modulate several behaviors associated with the 5-HT2A receptor.

A 2015 study showed that the CB1 receptor could form a functional heteromer with the 5-HT2A receptor. Activation of CB1 was able to co-activate the 5-HT2A receptor through dimerization. The heteromer was also able to activate different signaling pathways than either receptor on its own. In fact, this heteromer appears responsible for much of the deleterious effects of THC on memory, but also some of the anti-anxiety effect of low THC doses.

CB1 & Dopamine Receptors

CB1 and dopamine D2 receptors are coexpressed in the brain in the basal ganglia, an area involved in cognition, motor function, and emotional control.

CB1 receptors can form heteromers with D2 receptors in neurons (shown in a 2010 study and earlier studies). Simultaneous stimulation of both receptors resulted in increased heteromer formation and a switch in the intracellular signaling pathway that was activated. Persistent CB1 activation was also associated with a decrease in D2 receptor expression. The functional consequences of this remain unknown, but may have implications for the treatment of Parkinson’s Disease.

CB1 & Adenosine Receptors

A brain region called the dorsal striatum regulates motor activity, cognitive functions, and mood. Most of the neurons within this region express both the CB1 receptor and the adenosine subtype 2A (A2A) receptor.  The A2A receptor is famous as the receptor that is inhibited by caffeine.

Although there are many different interactions between the adenosine and endocannabinoid systems, a 2017 study showed that some of these interactions can be mediated by formation of a heteromer with CB1. Similar to the μOR, co-activation of both receptors led to a reduction in receptor signaling. This was also accompanied by a switch in the intracellular signaling pathway activated.

In Huntington’s Disease, there are changes in the expression and function of both CB1 and A2A in the dorsal striatum. The above study also showed that the CB1-A2A heteromer is selectively lost as Huntington’s Disease progresses to later stages. This may cause drugs acting on the cannabinoid or adenosine systems to have different effects early vs. late in the disease.

CB1 & Orexin Receptors

The orexin OX1 and OX2 receptors bind the neuropeptides orexin-A and orexin-B. These receptors regulate many functions which overlap with cannabinoids, including wakefulness and sleep, appetite, pain, and reward.

The CB1 receptor dimerizes with both the OX1 receptor and OX2 receptor. The OX1 receptor activation by an agonist was much more potent in the presence of the CB1 receptor. Activation of OX1 causes internalization of the OX1 receptor (this is a method of downregulating the receptor). When the CB1 receptor is expressed in the same cell, CB1 is also internalized through the heteromer, indicating the two receptors can be co-regulated. However, we must await further studies to see how this affects the biological functions listed above.

CB2 & Chemokine Receptors

Chemokine receptors generate signals that lead to cellular migration and proliferation. Although there are important roles for chemokine receptors in healthy tissues, they also can promote cancer cell development and metastasis. Expression of the chemokine CXCR4 receptor  on tumor cells is a negative prognostic factor associated with increased tumor aggressiveness, metastasis, and decreased probability of survival.

A 2016 study has shown that the CB2 and CXCR4 receptors can form heterodimers in breast and prostate cancer cells. Simultaneous activation of both receptors led to reduced CXCR4 signaling. Downstream effects of this included reduced cancer cell migration, which is an important step in metastasis. This study shows that receptor dimerization is a new mechanism of how cannabinoids can exert effects on tumors.

[Featured image: Flickr/ Flazingo Photos]

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Last modified: May 26, 2017

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