regulation, variation, CNS distribution and its emerging role in immuno-
endocannabinoid interactions with novel knowledge and deeper insight from the
genetic and epigenetic manipulation of CB2Rs. We conclude that CB2 cannabinoid
receptor signaling plays an important role in neuro-immuno-cannabinoid activity
and beyond (Onaivi et al. 2012 ) with potential therapeutic targets in neurological
and mental diseases.
10.2 Sub-type CB2 Cannabinoid Receptor Gene,
Gene Structure, Regulation and Variation
The CNR2genomic structure and CB2-receptor sub-type specificity has been
poorly defined. However, many features of theCNR2gene structure, regulation and
variation are beginning to emerge with the discovery and identification of CB2Rs in
mammalian CNS (Van Sickle et al. 2005 ; Gong et al. 2006 ; Onaivi et al.2008a,b;
Liu et al. 2009 ). This prior poor definition could be related to the previously held
view thatCNR2gene and CB2Rs were not expressed in neurons in brain but mainly
in immune cells. It was therefore less investigated for CNS roles except for the
association with brain cells of macrophage lineage. Our most striking discovery
aboutCnr2genomic structure is the species- and tissue- specific expression patterns
and differences between CB2R genes in human, rat and mouse (Liu et al. 2009 ;
Zhang et al. 2015 ). We found a novel human CB2A and CB2B isoform (Liu et al.
2009 ; Zhang et al. 2015 ). The CB2A isoform is predominantly expressed in human
brain and testis and the promoter of CB2A is located 45 kb upstream of the pro-
moter of the previously identified CB2R gene (which we now named CB2B iso-
form), that is predominantly expressed in spleen (Munro et al. 1993 ). In contrast,
we could not detect CB2B mRNA expression in brain regions in any significant
level and is predominantly expressed in spleen (Liu et al. 2009 ). This may be why
others were not able to detect CB2Rs in the brain, particularly in neurons, which
had been controversial (Ghose 2009 ; Atwood and Mackie 2010 ; Rogers 2015 ) but
now the issue of neuronal CB2R expression has been largely resolved (Van Sickle
et al. 2005 ; Gong et al. 2006 ; Onaivi et al.2008a,b; Liu et al. 2009 ; Stempel et al.
2016 ). It has been demonstrated that CB2Rs are expressed in hippocampal principal
cells and modulate neuronal function both in vitro and in vivo. We have also found
and reported that R63Q polymorphism inCNR2gene are associated with alco-
holism, depression, schizophrenia, and anorexia nervosa in Japanese subjects
(Ishiguro et al. 2007 ,2010a,b; Onaivi et al.2008a,b). These studies contribute to
the understanding not only of cell type specific functional roles of CB2Rs but also
providing insights into the molecular and behavioral effects associated with the
modulation of CB2Rs.
10 Cannabinoid CB2 Receptor Mechanism ofCannabis sativaL. 229