evidence showed significant species differences of CB2Rs in humans, mice and rats
in terms of peptides, mRNA sizes, gene structure and pharmacology (Brown et al.
2002 ; Munro et al. 1993 ; Shire et al. 1996 ). Therefore, the discrepancies on the
CB2R mRNA sizes in the literature indicated incomplete gene structure of CB2R
gene in different species or polymorphism in the same species. We have discovered
a novel humanCNR2gene promoter encoding testis isoform, CB2A starting exon
located ca 45 kb upstream from previously identified promoter encoding the spleen
isoform CB2B (Liu et al. 2009 ). The 5’ exons of both CB2-R isoforms are
untranslated 5’UTRs and alternatively spliced to the major protein coding exon of
CNR2gene. We found that CB2A is expressed at higher extent in testis and brain
than CB2B which in turn is expressed in other peripheral tissues more intensively
than CB2A. Using precise probes, species comparison found that theCNR2gene of
human, rat and mouse genomes deviated in their gene structures and isoform
expression patterns and could be regulated by cannabinoid ligand treatment in the
mouse model (Liu et al. 2009 ). The human CB2R gene is almost four times larger
than the mouse and rat CB2 genes. If the transcription rates are similar between
human and rodents, hCB2A isoform would take much longer time to be transcribed
in the testis and brain. This will be unusual because other gene orthologs between
humans and mice are usually within one fold difference in genomic sizes. Our data
shows that there are two forms of the CB2Rs in human, rat and mouse with
differential subtype distribution specificities in the brain and peripheral organ tis-
sues. The promoter-specific CB2R isoform distribution may in part explain why
CB2Rs were previously undetectable in both human and rodent brains (Brown et al.
2002 ; Galiegue et al. 1995 ; Munro et al. 1993 ).
ConditionalCnr1mutant mice (Marsicano et al. 2003 ; Monory et al. 2006 ;
Corbille et al. 2007 ; Albayram et al. 2011 ; Chiarlone et al. 2014 ; Zimmer 2015 )
have been produced and improved understanding of the mechanisms and functional
roles of CB1Rs. TheCnr1-floxed mice were used to produce cell-type specific
conditional (cKO) mouse lines. With these mice the function of CB1Rs have been
determined in specific neuronal circuits, in combination with viral expression
systems and in cell populations or to discriminate between peripheral and central
effects (Zimmer 2015 ). As many features CB2R function, variation and impact on
behavior remain poorly characterized compared to CB1Rs, the situation has started
to change with a new ground breaking research usingCnr2-floxed and Syn-Cre
mice to produce Syn1-Cnr2cKO mice (Stempel et al. 2016 ). The data from the
study confirmed the functional neuronal expression of CB2Rs in hippocampal
principal cells. As there are currently no cell-type specific cKO mice with deletion
of CB2Rs in dopamine neurons or in immune cells, we have generatedCnr2-floxed
and produced CB2R cKO mouse lines to examine specific functional roles of
CB2Rs in different molecular pathways in the nervous and immune systems
(Fig.10.2).
10 Cannabinoid CB2 Receptor Mechanism ofCannabis sativaL. 233