Genes encoding orthologs of the mammalian CB1 receptor have been identified in fishes, amphibians and birds, indicating that CB1 receptors may occur throughout the vertebrates. The genomes of the invertebrates Drosophila melano-gaster and Caenorhabditis elegans, however, do not contain CB1 orthologs, indicating that CB1-like cannabinoid receptors may have evolved after the divergence of deuterostomes and protostomes.
The cDNA of the CB1-receptor is 5.7 kb in length and encodes for a putative protein which contains seven hydrophobic domains. The CB1 receptor (Fig. 4.4) is coupled to G proteins of the Gi/Go type. Anandamide and endocannabinoids appear to bind to CB1 receptors in transmembrane alpha helices 2, 3, 4 and 5, leading to the inhibition of the activity of adenylate cyclase, which gives rise to a subsequent inhibition of cAMP production.
Electrophysiological studies reveal that anandamide, via CB1 receptor binding, inhibits high-voltage-activated calcium channels (so-called N-type channels). CB1 receptors are primarily expressed at presynaptic sites and thus allow modulation of neurotransmitter release through retrograde signaling by endocannabi-noids. Such a modulation was described in the cerebellum and the hippocampus, where the activation of CB1 receptors elicits a depolarization-induced suppression of inhibition (DSI). DSI represents a short inhibition of neurotransmit-ter release which is initiated by the postsynaptic release of endocannabinoids.
The secretion of endocannabinoids is stimulated through postsynaptic increase of intracellular calcium by:
1. Activation of voltage-sensitive calcium channels which stimulates the production of endocannabinoids via phospolipase D.
2. Receptor-mediated release where activation of metabotropic glutamate or nico-tinergic acetylcholine receptors seem to be involved. The latter pathway is G protein-dependent and requires phospholipase C.
This receptor-driven pathway is responsible for endocannoabinoid-mediated long-term depression (LTD). Also, the facilitation of LTP production through en-docannabinoid release has been described for CA1 neurons, indicating that these neuromodulators play a substantial role in modulating synaptic efficacy in different cell types and brain regions (Fig. 4.5).
CB1 receptors exhibit binding specificity to anandamides, but they can also bind several other endogenous ligands which are present in the central nervous system. These substances include homo-y-linolenyl-ethanolamide and docosate-traenyl-ethanolamide, as well as 2-arachidonylglycerol, all of which bind to both CB1 receptors and CB2 receptors.
The human CB1 receptor and the CB1 receptor of rats share a homology of 97.3% in their amino acid sequence. The distribution of CB1 receptors in the human central nervous system and in the central nervous system of rats is quite similar.
CB1 receptors have been identified within the cortex, the olfactory bulb, the hippocampal formation, the caudate-putamen, the globus pallidus, the substan-tia nigra, the nucleus accumbens, the entopeduncular nucleus and the molecular layer of the cerebellum (Fig. 4.6).
Fig. 4.5 Retrograde signaling by endocanna-binoids. Postsynaptic depolarization opens voltage-dependent Ca2+ channels. An increase in postsynaptic Ca2+ elicits an activation of phospholipase D, which leads to endocannabinoid synthesis from lipid precursors. Activation of postsynaptic mGluRs can also generate endo-cannabinoids. A pathway which seems to involve phospholipase C and the generation of diacylglycerol is further cleaved by
Fig. 4.5 Retrograde signaling by endocanna-binoids. Postsynaptic depolarization opens voltage-dependent Ca2+ channels. An increase in postsynaptic Ca2+ elicits an activation of phospholipase D, which leads to endocannabinoid synthesis from lipid precursors. Activation of postsynaptic mGluRs can also generate endo-cannabinoids. A pathway which seems to involve phospholipase C and the generation of diacylglycerol is further cleaved by diacylglycerol lipase to yield 2-arachidonyl-glycerol. Endocannabinoids then leave the postsynaptic cell and work as retrograde messengers by activating presynaptic CB1 receptors. Postsynaptic G protein activation liberates G^, which then directly inhibits presynaptic Ca2+ influx. This decreases the probability of release of a vesicle of neurotransmitter (adapted from Wilson and Nicoll 2002).
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