The evolution and comparative neurobiology of endocannabinoid signalling

Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3201-15. doi: 10.1098/rstb.2011.0394.


CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1)-type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Evolution*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiology
  • Carrier Proteins / classification
  • Carrier Proteins / metabolism
  • Endocannabinoids / metabolism*
  • Endocannabinoids / pharmacology
  • Humans
  • LIM Domain Proteins / classification
  • LIM Domain Proteins / metabolism
  • Learning / physiology
  • Motor Activity / physiology
  • Neurobiology / methods
  • Neurotransmitter Agents / pharmacology
  • Phylogeny
  • Presynaptic Terminals
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism
  • Signal Transduction*


  • CRIP1 protein, human
  • Carrier Proteins
  • Endocannabinoids
  • LIM Domain Proteins
  • Neurotransmitter Agents
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2