Cannabinoids and Their Receptors

Abstract

Phytocannabinoids are ∼100 molecules with a similar structural motif found in cannabis. The best known of these is Δ9‐tetrahydrocannabinol (Δ9‐THC), the chief psychoactive component of cannabis. In 1989, the first ‘cannabinoid’ receptor was identified. This first receptor, christened CB1, has since been joined by several others: CB2, GPR18 and GPR119. These receptors mediate the effects of THC but are also part of an endogenous signalling system. The human body makes endogenous cannabinoids; lipid messengers that are structurally distinct from phytocannabinoids and that are synthesised and metabolised enzymatically. This combination of cannabinoid receptors, endocannabinoids and proteins to synthesise, transport and metabolise these receptors form an important endogenous signalling system with roles in the brain and throughout the body. The cannabinoid signalling system regulates numerous functions including memory, motor control, appetite, nausea and pain.

Key Concepts

  • Δ9‐THC is a plant cannabinoid that acts on the body by plugging into an endogenous signalling system in the body.
  • Δ9‐THC is one of ∼100 ‘phytocannabinoids’ including cannabidiol (CBD) that are an area of active research.
  • Established cannabinoid receptors are G‐protein‐coupled receptors (GPCRs) that transmit an extracellular chemical signal into an intracellular cascade via second messengers.
  • Cannabinoid receptors are found in much of the brain and throughout the body where they play numerous physiological roles.
  • Endogenous cannabinoids are lipid messengers that are structurally unrelated to Δ9‐THC.
  • Unlike classical neurotransmitters, endocannabinoids are not stored in or released from vesicles but are instead produced ‘on‐demand’ and subsequently metabolised by enzymes.
  • Cannabinoid enzymes synthesise or metabolise families of cannabinoid‐related lipids rather than a single endocannabinoid.
  • The ubiquity of cannabinoid receptors in the body and the legal status of cannabinoids have made development of cannabinoid‐based therapeutics difficult.

Keywords: cannabinoid; CB1; CB2; anandamide; 2‐AG; cannabis; marijuana

Figure 1. Structures of three cannabinoids. Chemical structures of Δ9‐tetrahydrocannabinol (Δ9‐THC) the chief psychoactive ingredient of marijuana and hashish; WIN‐55212‐2 a synthetic agonist of the cannabinoid CB1 receptor; 2‐arachidonoyl glycerol (2‐AG), an endocannabinoid. Note that although all cannabinoids are lipophilic, their structures can be quite different. Δ9‐THC does not resemble putative endogenous cannabinoids 2‐AG or anandamide.
Figure 2. Depolarisation‐induced suppression of excitation (DSE). Schematic of pre‐ (top) and postsynaptic terminals. Standard action potential‐induced neurotransmitter release (using glutamate as example) occurs via activation of calcium channels linked to transmitter‐filled vesicles which fuse with the membrane to release their contents. Glutamate then acts on assorted postsynaptic glutamate receptors. In contrast, DSE involves depolarisation‐induced postsynaptic production of endocannabinoids (eCBs) (anandamide or 2‐AG – the latter shown as example). A favoured mechanism involves activation of the enzyme DAG lipase (DAGL), converting diacylglycerol (DAG) into 2‐AG. Rather than being released from vesicles, lipophilic eCBs appear to cross the membrane via facilitated diffusion across a transporter. The mechanism of subsequent transport across the synapse is unknown but may involve chaperone proteins. Activation of presynaptic CB1 receptors inhibits action potential‐induced transmitter release by inhibiting Ca2+ channels.
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Straiker, Alex(Jan 2020) Cannabinoids and Their Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000030.pub2]