Introduction Although G protein coupled receptor GPR was con
Although G-protein-coupled receptor 55 (GPR55) was considered a cannabinoid receptor, it differs phylogenetically from cannabinoid type 1 (CB1) and type 2 (CB2) receptors as it lacks the classic cannabinoid-binding pocket (Baker et al., 2006). GPR55 is sensitive to an array of cannabinoids (Petitet et al., 2006, Lauckner et al., 2008), although the most consistently described agonist is the endogenous lipid, lysophosphatidylinositol (LPI) (Oka et al., 2007, Henstridge et al., 2009). Despite discrepancies in downstream signaling of GPR55, a growing body of evidence points to the involvement of both G12 and G13 proteins that activate RhoA and mobilize Ca2+ (Ryberg et al., 2007, Lauckner et al., 2008, Henstridge et al., 2009), probably in an agonist- and tissue-dependent manner (Ross, 2009).
GPR55 mRNA has been described in different regions of the mouse and human nervous system (Ryberg et al., 2007, Henstridge et al., 2011, Wu et al., 2013). GPR55 is involved in dorsal root ganglia excitability (Lauckner et al., 2008), in axon growth and in the target innervation of retinal projections during development (Cherif et al., 2015), as well as in procedural memory (Marichal-Cancino et al., 2016). The significant niclosamide in the striatum suggests an important role of GPR55 in this region. In fact, the motor behavior of mice lacking GPR55 is impaired (Wu et al., 2013, Meadows et al., 2015, Bjursell et al., 2016). These mice also develop less severe experimental colitis (Schicho et al., 2011) and there is an absence of inflammatory response or mechanical hyperalgesia in a model of neuropathic hypersensitivity (Staton et al., 2008). Together, these data support a relevant role for this receptor in the regulation of both neural transmission and neuroinflammation.
Pharmacological studies of cannabidiol (CBD) have shown a wide range of actions in different systems and in neurodegenerative diseases (McPartland et al., 2015, Iuvone et al., 2009). In the hippocampus, CBD may prevent the pro-inflammatory glial cell activation induced by the amyloid beta administration (Esposito et al., 2007). Moreover, administration of CBD attenuates the dopaminergic system impairment that follows to a lesion with 6-hydroxydopamine (6-OHDA) in rats, that effect was attributed to the anti-inflammatory and anti-oxidant properties of CBD (Lastres-Becker et al., 2005). However, a clinical trial using a standardized plant extract containing CBD showed that the treatment, despite being well tolerated by patients with Parkinson's disease (PD), it lacked pro- or anti-parkinsonian effects (Carroll et al., 2004). Abnormal-cannabidiol (Abn-CBD) is a synthetic CBD isomer that binds to GPR55 (Johns et al., 2007, Ryberg et al., 2007, McKillop et al., 2013). This isomer has vasoactive properties (Su et al., 2015), as well as a glucose-lowering and insulinotropic capacity (McKillop et al., 2013, McKillop et al., 2016), and therapeutic potential in the treatment of inflammatory bowel diseases (Krohn et al., 2016).
Materials and methods
Discussion The expression of GPR55 in mouse tissue has been described by quantitative PCR, showing a broad distribution in the nervous system that includes the frontal cortex, striatum, hippocampus and cerebellum (Ryberg et al., 2007, Wu et al., 2013). Northern blot analysis in human brain tissues demonstrated the presence of GPR55 mRNA in the caudate and putamen, while there was no evidence of GPR55 transcripts in the frontal cortex, pons, hippocampus, thalamus or cerebellum (Sawzdargo et al., 1999). GPR55 mRNA is expressed in primary cultures of mouse microglia cells and by a murine microglial cell line, and its expression is regulated by LPS or INFγ (Pietr et al., 2009). Activation of microglial GPR55 with LPI exerts a neuroprotective activity on organotypic hippocampal slice cultures (Kallendrusch et al., 2013). The use of in situ hybridization to detect GPR55 transcripts confirmed the expression of GPR55 in the mice striatum, cortex and hippocampus described previously, and these studies provided additional evidence for its presence in the GPe, STN and SN. Furthermore, GPR55 transcripts co-localized with the neuronal marker NeuN, whereas no expression was detected in astroglia or microglia in the striatum or midbrain. The higher sensitivity of PCR compared to Northern blotting or ISH to detect GPR55 transcripts, and the different nature of samples (cell cultures vs brain tissue) may account for these differences. The expression of GPR55 was profoundly downregulated in the striatum of the mouse PD models, suggesting that GPR55 might be involved in the pathology of this disease. However, downregulation of GPR55 expression in the midbrain seemed to be related to the loss of dopaminergic neurons, since no changes in GPR55 expression were detected in the remaining SNpc neurons.