Biology Reference
In-Depth Information
of CB3 is yet to come. cDNA sequences encoding CB1- or CB2-like receptors have been
reported for the rat [139], human [72, 151], mouse [1, 41], cow (Wessner, GeneBank
submission, 1997), cat [71] (GeneBank submission, 1997), puffer fish [214], leech [183],
zebra finch [181], and newt [182]. Although significant progress has been achieved into many
aspects of the biology of the endocannabinoid system, and our knowledge of cannabinoid
genomics and proteomics is increasing, the regulation of cannabinoid receptor genes is poorly
understood.
The CB1 receptor is mainly expressed in the brain and spinal cord and thus is often
referred to as the “brain cannabinoid receptor”. The CB2 receptor is sometimes referred to as
the “peripheral cannabinoid receptor” because initial studies suggested that CB2 receptors
were predominantly present in immune cells in the periphery [67, 151]. Recent studies
suggested that CB2 cannabinoid receptors are functionally expressed in neurons in the brain
[66, 78, 92, 161, 199]. CB1 receptors are among the most abundant G-protein-coupled
receptors in the brain, their densities being similar to the levels of γ-aminobutyric acid
(GABA)- and glutamate-gated ion channels [91]. CB1 receptors have been shown to be
localized presynaptically on GABAergic interneurons and glutamatergic neurons [83, 84,
107, 108] and is believed to mediate most of the effects described in this chapter. This would
be consistent with the proposed role of endocannabinoid compounds in modulating
neurotransmission.
(a) The signal transduction mechanism of cannabinoid receptors
Activation of a cannabinoid receptor promotes its interaction with G proteins, resulting in
guanosine diphosphate/guanosine triphosphate exchange and subsequent dissociation of the α
and βγ subunits. These subunits regulate the activity of multiple effector proteins to bring
about biological functions (Fig. 1). CB1 is coupled with G
i
or G
o
proteins. CB1 receptors
differ from many other GPCR proteins in being constitutively active, as they are precoupled
with G-proteins in the absence of exogenously added agonists [149]. Among its cellular
actions are inhibitions of
adenylate cyclase activity [44, 99, 163], inhibition of N- type voltage-gated channels [39,
125, 155, 162], inhibition of N-type, P/Q-type calcium channels and D-type potassium
channels [98, 99], activation of A-type and inwardly rectifying potassium channels [148] and
inhibition of synaptic transmission [68, 98]. Based on these findings, it has been suggested
that CB1 receptors play a role in regulation of neurotransmitter release [68, 98].
In addition, one of the most interesting research areas is the regulation of neuritogenesis,
axonal growth and synaptogenesis by CB1 receptors.
The molecular mechanism involved in
this process is not yet clear. The CB1 receptor activates MAPK pathway [209]. In some cells,
CB1 receptor-mediated activation of MAPK was mediated through the PI3 kinase pathway
[27, 209]. AEA, CP,55, 940 and WIN 55,212-2 increased phosphorylation of FAK+ 6,7, a
neural isoform of FAK, in hippocampal slices and in cultured neurons [54]. CB1 receptor
activation stimulate phosphorylation of the Tyr-397 residue of FAK in the hippocampus,
which is crucial for FAK activation [55] and increase phosphorylation of p130-Cas, a protein
associated with FAK in the hippocampus. CB1 receptor-stimulated FAK-autophosphorylation
was shown to be upstream of the Src family kinases [55]. These new downstream effectors of
CB1 receptors are quite likely play a role in some forms of synaptic plasticity through gene
regulation, but needs further investigation.
