THE ROLE & MECHANISM OF RECEPTOR SYSTEMS

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The twentieth century can be regarded as the golden age of scientific discovery for how and why human receptor systems function. Exploration continues, with an eye to better understandings of how a receptor’s functions can be targeted not just with medicines that operate directly on the receptors, but also with treatments that enhance, inhibit, or block the metabolism of natural substances that interact with these unique receptors.

While receptors and the natural ligands that attach to them are often described as locks and keys, molecules of other substances that are capable of activating those receptors need not resemble the molecular structure of natural ligands. The lock-and-key metaphor for describing an endocannabinoid receptor’s activation can seem misleading when exogenous ligand molecules produce differing degrees of receptor engagement.

CB1 receptor’s central binding site and stabilizing research molecule shown in green, surrounded by other test molecules, natural ligands Anandamide & 2-AG, and cannabis plant-derived Δ-9 tetrahydrocannabinol (THC). (Yekaterina Kadyshevskaya, Stevens Laboratory, USC)

The ‘orthosteric’ receptor site is where the primary interaction occurs between that receptor and either its natural ligand, or a drug that produces direct agonism or antagonism of that receptor. Agonists, which activate the receptor, and antagonists, which can counter-balance the receptor’s action, operate at these specific sites. For some receptors, equally important are their ‘allosteric’ receptor sites, alternative areas to which therapeutic molecules can bind in order to modulate selective innate effects of the receptor’s activation. Allosteric modulators offer significant therapeutic promise for leveraging endogenous receptor function, without otherwise causing the consequences of unnatural receptor activation.

A MASTER REGULATORY RECEPTOR SYSTEM

Among the receptor systems identified in the last century, several have important implications for treatment, such as the dopamine and serotonin systems. But none hold quite the significance of the endogenous cannabinoid system (ECS), as it plays a regulatory role with other bodily systems that maintains the physiological balances of homeostasis 1.

Cannabinoid receptors are part of the Class A family of G Protein Coupled Receptors (GPCR), which are implicated in nearly all physiological functions of the peripheral and central nervous systems, and in various peripheral organs. The ECS fulfills an essential regulatory role in the body’s biochemistry and physiology, operating to maintain physiological system balances by keeping their functions within tenable parameters. Many different types of receptors can influence the activity of one another by enhancing or inhibiting their effects, but the ECS operates as a constant fine-tuning master system that attenuates the action of all other receptor systems, including those of the endorphin receptor system central to stress and pain responses 2.

Cannabinoid receptors are so ubiquitous and important, a recent NIH review concluded that “modulating ECS activity may have therapeutic potential in almost all diseases affecting humans” 3. In summary, the ECS is the central regulatory system for maintaining a physiological balance sometimes referred to as homeostasis, not only in mammals, but also in all animals 4,5. The components of the ECS are expressed in nearly all parts of the human body throughout every stage of life, and they exert influence on nearly all other receptor systems’ neurotransmitters, such as dopamine, serotonin, melatonin, and acetylcholine 6-7.

ost-synaptic neuron retrograde cannabinoid signaling at the synapse serves as a feedback loop. (Phytecs, Inc.; artwork by John Karapelou.)

THE UBIQUITOUS ECS

The abundance of cannabinoid receptors in the human body is most remarkable, with roughly four times more than dopamine D2 receptors and twelve times more than mu-opiate receptors. The ECS differs from other receptor systems not just by being the only lipid-based neurotransmitter system; it is also unique in that it has not one, but two ligands that exert their collective effects at two principal types of lipophilic cannabinoid receptors designated as CB1 and CB2. By comparison, the dopaminergic system has a single ligand neurotransmitter, dopamine, that is capable of acting on five different receptors, while endorphins are known to act on at least 20 different receptors 8.

The ECS also employs a unique retrograde feedback loop to affect pre-synaptic signaling. Both of the endogenous cannabinoids: N-arachidonylethanolamine (AEA) also known as anandamide – dubbed ‘anandamide’ from the Sanskrit word for “bliss” – and 2-arachidonylglycerol (2-AG) are found in the post-synaptic neuron membrane within a lipid ring encircling synapses that keep the endocannabinoids and their receptors sequestered from their aqueous surroundings. They are produced on-site and on-demand. These cannabinoids then travel retrograde, backwards to the pre-synaptic cannabinoid receptor associated with that transmitting neuron to modulate the release of all neurotransmitters, including glutamate.

 Concentrations of localized CB2 receptors appear in the brain in connection with its injury, as well as neurodegenerative conditions such as Parkinsonism. After a head injury or stroke that may frequently produce cell death, endocannabinoids produced at that site of brain injury mitigate the increase of glutamate signaling. Expression of CB2 receptors in response to inflammation or injury is not limited to the brain. Glutamate manipulation may hold significance for pain management because overproduction of this stimulatory chemical is also implicated in neuropathic pain associated with conditions such as diabetes, multiple sclerosis, HIV/AIDS, and cancer 9.

Considerably more work is needed to fully describe the pharmacology of the orthosteric and allosteric modulators operating on the ECS, but much is already known. The endocannabinoid anandamide is a partial agonist, operating as a modulator more in the periphery, outside the CNS. Anandamide functions as a partial receptor agonist affecting the neurons that regulate pain signaling by controlling the chemical gates through which pain signals access the CNS.

By contrast, the endocannabinoid 2-AG is a total agonist, fully activating the cannabinoid receptors. 2-AG has been referred to as the workhorse of the ECS, serving as a point-to-point retrograde messenger to provide fundamental brain and spinal cord functions. Major endocannabinoids are rapidly deactivated by reuptake mechanisms and degrading enzymes 10,11. Cannabinoid receptor activity is also selectively modified by the binding of ligands at allosteric sites on receptors.

ECS signaling is generally linked to cell proliferation, cell differentiation, cell movement, and cell death 12. Cannabinoid receptors are most abundant on the cell surface’s plasma membranes, as well as on the endoplasmic reticulum and around the cell nucleus. Cannabinoid receptors may also be present on other organelles within the cell, including mitochondria 13. The locations and activities of CB1 receptors are highly dynamic, allowing significant effects derived from receptor signaling. CB1 receptors are ubiquitous in the CNS, peripheral nerve terminals, and within some extra-neuronal sites, with concentrations in areas that agree with what is known about cannabinoid effects on neurophysiology 10,14.

Knowing the relationship between the CB receptors and cannabinoid medicines enables us to give sound medical advise of the effects of their uses in the medical field. Complete the enquiry form at the bottom of the page to take advantage of our medical cannabinoid consultancy services.


References

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2. Befort K. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies. Front Pharmacol. 2015;6(6).

3. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease–successes and failures. FEBS J. 2013;280(9):1918-1943.

4. Elphick MR. The evolution and comparative neurobiology of endocannabinoid signalling. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3201-3215.

5. Vaughn L, Denning G, Stuhr K, de Wit H, Hill M, Hillard C. Endocannabinoid signalling: has it got rhythm? Br J Pharmacol. 2010;160(3):530-543.

6. Russo EB. The role of cannabis and cannabinoids in pain management. In: BE C, M B, eds. Weiner’s Pain Management: A Practical Guide for Clinicians. Boca Raton, FL: CRC Press; 2006:823–844.

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8. Dalayeun JF, Norès JM, Bergal S. Physiology of beta-endorphins. A close-up view and a review of the literature. Biomed Pharmacother. 1993;47(8):311-320.

9. Russo E. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245-259.

10. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3353-3363.

11. Piomelli D. The molecular logic of endocannabinoid signalling. Nature Reviews Neuroscience. 2003(4):873-884.

12. Prenderville JA, Kelly ÁM, Downer EJ. The role of cannabinoids in adult neurogenesis. Br J Pharmacol. 2015;172(16):3950-3963.

13. Busquets-Garcia A, Bains J, Marsicano G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacology. 2017;43:4.

14. Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):4-15.

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