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The neurobiology and evolution
of cannabinoid signalling
by
Elphick MR, Egertova M.
ABSTRACT
The plant Cannabis sativa has been used by humans
for thousands of years because of its psychoactivity. The major psychoactive
ingredient of cannabis is Delta(9)-tetrahydrocannabinol, which exerts effects
in the brain by binding to a G-protein-coupled receptor known as the CB(1)
cannabinoid receptor. The discovery of this receptor indicated that endogenous
cannabinoids may occur in the brain, which act as physiological ligands
for CB(1). Two putative endocannabinoid ligands, arachidonylethanolamide
('anandamide') and 2-arachidonylglycerol, have been identified, giving rise
to the concept of a cannabinoid signalling system. Little is known about
how or where these compounds are synthesized in the brain and how this relates
to CB(1) expression. However, detailed neuroanatomical and electrophysiological
analysis of mammalian nervous systems has revealed that the CB(1) receptor
is targeted to the presynaptic terminals of neurons where it acts to inhibit
release of 'classical' neurotransmitters. Moreover, an enzyme that inactivates
endocannabinoids, fatty acid amide hydrolase, appears to be preferentially
targeted to the somatodendritic compartment of neurons that are postsynaptic
to CB(1)-expressing axon terminals. Based on these findings, we present
here a model of cannabinoid signalling in which anandamide is synthesized
by postsynaptic cells and acts as a retrograde messenger molecule to modulate
neurotransmitter release from presynaptic terminals. Using this model as
a framework, we discuss the role of cannabinoid signalling in different
regions of the nervous system in relation to the characteristic physiological
actions of cannabinoids in mammals, which include effects on movement, memory,
pain and smooth muscle contractility. The discovery of the cannabinoid signalling
system in mammals has prompted investigation of the occurrence of this pathway
in non-mammalian animals. Here we review the evidence for the existence
of cannabinoid receptors in non-mammalian vertebrates and invertebrates
and discuss the evolution of the cannabinoid signalling system. Genes encoding
orthologues of the mammalian CB(1) receptor have been identified in a fish,
an amphibian and a bird, indicating that CB(1) receptors may occur throughout
the vertebrates. Pharmacological actions of cannabinoids and specific binding
sites for cannabinoids have been reported in several invertebrate species,
but the molecular basis for these effects is not known. Importantly, however,
the genomes of the protostomian invertebrates Drosophila melanogaster and
Caenorhabditis elegans do not contain CB(1) orthologues, indicating that
CB(1)-like cannabinoid receptors may have evolved after the divergence of
deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic
analysis of the relationship of vertebrate CB(1) receptors with other G-protein-coupled
receptors reveals that the paralogues that appear to share the most recent
common evolutionary origin with CB(1) are lysophospholipid receptors, melanocortin
receptors and adenosine receptors. Interestingly, as with CB(1), each of
these receptor types does not appear to have Drosophila orthologues, indicating
that this group of receptors may not occur in protostomian invertebrates.
We conclude that the cannabinoid signalling system may be quite restricted
in its phylogenetic distribution, probably occurring only in the deuterostomian
clade of the animal kingdom and possibly only in vertebrates.
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