10.3 Diversification of CBR Genes, Expression
and Function in Human, Rhesus Monkey,
Dog, Rat and MouseCB2 cannabinoid receptor is not exclusively a peripheral cannabinoid as previously
thought and overwhelming scientific data indicate that just like CB1Rs, CB2Rs are
distributed in normal brain and peripheral tissues. It has become clear that while the
expression of CB2Rs in the brain is much less than CB1Rs (Gong et al. 2006 ;
Onaivi 2011 ), CB2R expression is induced during inflammation. Recent studies
suggest that cannabinoids may produce different pharmacological actions in
experimental species, suggesting that cannabinoid effects in one species cannot be
directly extrapolated to another species Zhang et al. ( 2015 ). We hypothesize that
species differences in CB1R and CB2R expression, protein structure and function
may contribute to different pharmacological actions produced by cannabinoids in
different species. Using quantitative RT-PCR, we found species-specific differential
expression of CB1R and CB2R isoforms in brain regions and peripheral tissues.
Human, rhesus monkey and ratCnr2genes encode 360 amino acids while mouse
Cnr2gene encodes 347 amino acids with a premature stop codon at its C-terminus.
Based on thesefindings, we predict that different promoters, epigenetic signatures,
exons and/or different sequences in 5’-UTR and 3’-UTR of different isoforms may
alter CB1R/CB2R receptor expression in different tissues, brain regions and/or
different cellular types, and therefore, contribute to different CB1R/CB2R receptor
responses and signaling in different species. Computer modeling of the 3-D
structures found significant species differences in receptor structures such as
opposite charged amino acid residues located in the vicinities of putative ligand
binding sites. It is not surprising that different species display different pharma-
cological responses to the same ligands suggesting significant species differences in
cannabinoid receptor structures and functions.
There are also differentCNR2transcript isoforms depending on the species that
display significant differences in gene structures and brain expression patterns from
mouse to humans. HumanCNR2 (hCB2R) and mouseCnr2(mCB2R) genes
transcribe two isoforms—hCB2A and hCB2B, and mCB2A and mCB2B, respec-
tively, while ratCnr2(rCB2R) gene transcribes at least four isoforms—rCB2A,
rCB2B, rCB2C, and rCB2D (see Fig.10.1). Human hCB2A and hCB2B transcripts
are enriched in testis and spleen, respectively. Rat and mouse CB2A and CB2B
transcripts are both enriched in spleen. Mouse brain expresses mCB2AR and
mCB2BR isoforms with mRNA level of mCB2AR, higher than that of mCB2BR in
several brain regions. Mouse CB2R truncates 13 amino acids in the
carboxyl-terminal motif containing autophosphorylation sites (Ser 352) that is
involved in cellular internalization. The cloning and pharmacological characteri-
zation of other species (Onaivi et al. 2006 ) including the dog CB2R (dCB2R) have
been described, with similar 360 amino acid sequence with hCB2R (Ndong et al.
2011 ). The dCb2R shares between 76 and 82% homology with rat, mouse, human
and chimpanzee CB2Rs (Ndong et al. 2011 ). The effects of cannabinoids from one
230 E.S. Onaivi et al.