2'-O-Methyl-ATP br Action of GPR in metabolically active

Action of GPR55 in metabolically active tissues In addition to being highly expressed by discrete brain regions, as described in Section 2, GPR55 is also expressed in a wide range of peripheral tissues, including spleen, adrenals and bone (Sawzdargo et al., 1999, Ryberg et al., 2007, Whyte et al., 2009), and also in metabolically important cells such as adipocytes (Moreno-Navarrete et al., 2012), and those of the gastrointestinal tract (Ryberg et al., 2007, Lin et al., 2011, Schicho et al., 2011) and islets (Romero-Zerbo et al., 2011, Mckillop et al., 2013). As for identification of GPR55 in the brain, much of the work on the presence of GPR55 in peripheral tissues has focused on mRNA expression, but some studies have made use of GPR55 2'-O-Methyl-ATP to identify protein expression. For example, GPR55 expression has been identified by western blotting in human visceral adipose tissue, and shown to be increased in obese individuals and those with type 2 diabetes (Moreno-Navarrete et al., 2012). In addition, GPR55 has been detected in mouse osteoclasts by fluorescence immunohistochemistry, and specificity of the antibody used was confirmed by the lack of immunoreactivity in osteoclasts that were generated from bone marrow macrophages from GPR55 knockout mice (Whyte et al., 2009). Similarly, it has been demonstrated by immunohistochemistry that GPR55 is expressed by islet β-cells, but not by neighbouring α- or δ-cells, in wild type pancreas but not in pancreas from GPR55 null mice (Romero-Zerbo et al., 2011). Our current understanding of the contribution of this receptor to the maintenance of energy balance is discussed below and summarised in Fig. 2.
Conclusions and perspectives Although GPR55 was initially classified as a third cannabinoid receptor its sequence and ligand profile (Table 1) demonstrate that it does not sit neatly in this classification, and it has yet to find a suitable GPCR family. In some respects its effects in tissues involved in energy homeostasis mirror those of CB1, given that it has been implicated not only in the potentially deleterious effects of weight gain and fat storage, but also in beneficial action at β-cells to stimulate insulin secretion. However, full interpretation of studies is limited by the lack of specificity of many of the agonists and antagonists used to date, and future work in this area would benefit from the use of GPR55−/− mice and newly developed ligands with improved specificity (Table 1). It is worth noting that under physiological conditions GPR55−/− mice do not have a metabolic phenotype so investigating glucose tolerance in GPR55−/− mice in both normal and pathological conditions such as diet-induced obesity would therefore provide further insights into defining the role of GPR55 in maintaining energy homeostasis.
Conflict of interest statement
Introduction GPR55 is a G-protein coupled receptor (GPCR) initially identified as a new atypical cannabinoid target [1] modulated by endogenous and small synthetic ligands. GPR55 has the ability to interact with cannabinoid ligands despite sharing a relatively low amino acid sequence identity to CB1 (13.5%) and CB2 (14.4%) [2]. Interestingly, a non-cannabinoid lipid signaling molecule, lysophosphatidylinositol (LPI) was also identified as an endogenous agonist [3]. This finding has led to GPR55 provisional IUPHAR nomenclature with the receptor name LPI1 and gene name LPIR1/Lpir1 for human and non-human genes, respectively [4]. GPR55 is widely distributed in the brain and in peripheral tissues suggesting its involvement in various biological and pathological actions. At the peripheral level the expression has been detected throughout the gastrointestinal tract, in the liver, insulin-secreting pancreatic β cells, the adipose tissue, osteoclasts and osteoblasts as well as in cartilage tissues and immune cells [5]. Importantly, high expression levels of GPR55 have been associated with tumorigenesis and metastasis. GPR55 has been detected in breast tumors, in ovarian (OVCAR3 and A2780) and prostate (PC-3 and DU145) cancer cell lines, glioblastomas and other cancers [6].