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  • It appears that different agonists for


    It appears that different agonists for GPR55 activate different signalling pathways [25]. GPR55 activation through LPI has been shown to trigger ERK 1/2 phosphorylation 22, 23, 25, 33. Conversely, endogenous cannabinoid compounds AEA and 2-AG have been shown to have no effect on ERK 1/2 signalling 22, 23, 24, except at a supraphysiological dose [36], in which GPR55 activation using AEA (10μm) stimulated ERK1/2 [33]. Alternatively, synthetic cannabinoid agonists for GPR55, AM251 and SR141716A have both also been shown to activate ERK1/2 signalling [25]. GPCRs have the ability to form heteromers [42], which can result in changes to the subsequent downstream signalling pathways stimulated compared with homomers of the GPCRs [42]. The concept that GPCRs can form heteromers has further implications pharmacologically, because modulating a specific receptor might influence other receptor(s) and, therefore, result in altered cellular signalling [42]. A recent study indicated that CB1 can form a heteromer with GPR55 in HEK293 2,4-Diacetylphloroglucinol receptor [39]. In isolation, GPR55 activation using both LPI and SR141716A in vitro induced NFAT and SRE stimulation. However, in the presence of CB1, the activation of NFAT and SRE by LPI was significantly reduced [39]. Furthermore, in the presence of CB1, treatment with either SR141716A (a known antagonist and/or inverse agonist for CB1[43] and agonist for GPR55 [22]), or the selective GPR55 agonist GSK319197A, failed to activate NFAT and SRE [39]. In addition, with in vitro expression of both CB1 and GPR55, GPR55-mediated ERK1/2 phosphorylation was inhibited but CB1-mediated ERK1/2 phosphorylation was enhanced [39]. This suggests that, when CB1 is in the presence of GPR55, there is enhanced CB1 signalling [39]. Interestingly, when CB1 and GPR55 coexist, WIN55,212-2 and AEA (agonists for both GPR55 and CB1) reinstate GPR55 signalling. This study suggests that, when CB1 is blocked in vitro, GPR55 signalling is inhibited; however, when CB1 is activated, there is no effect on GPR55-mediated signalling. Investigation is required to determine whether the same signalling pattern mediated by CB1 and GPR55 occurs in vivo. Nonetheless, the finding that CB1 and GPR55 form a heteromer in vitro should be taken into consideration when describing the role of these receptors in obesity and related states of disordered metabolism. The endocannabinoid system is overactive in the obese state. 2-AG levels in plasma and visceral adipose tissue are elevated in obese individuals 7, 44. Both AEA and 2-AG have been demonstrated to activate CB1[2]. It could be hypothesised that, if there is coexpression of the receptors in the presence of an overactive endocannabinoid system, GPR55-mediated signalling should not be altered because CB1 is also activated [39]. Further investigation into the ability of CB1 and GPR55 to form heteromers in vivo is needed to demonstrate the significance of this interaction in homeostasis, as well as in disease states. GPR55 has also been demonstrated to interact with CB2[45]. Both GPR55 and CB2 are coexpressed in human neutrophils and, when both receptors are activated, there is enhanced cellular signalling of RhoA and Cdc42 and reduced signalling of Ras-related C3 botulinum toxic substrate 2 (Rac2) [45]. This crosstalk between GPR55 and CB2 signalling might occur in other tissues and could have implications for other cellular functions, such as cellular energy metabolism. Importantly, this is likely to occur in tissues where both CB2 and GPR55 are coexpressed, such as metabolically active tissues, including adipose tissue, liver, pancreas and skeletal muscle. Taken together, these studies suggest that GPR55 signalling is influenced by CB1 and CB2.
    Concluding remarks
    Introduction Recent advances in cancer biology have established that tumors are composed of continuously evolving heterogeneous populations with varying fitness [1], [2], [3]. This understanding is also reflected in the move from non-specific cytotoxic agents to target-specific drugs [4], [5]. However, while target-directed therapies have proven to be extremely successful, broad genetic diversity of tumor populations still require use of multi-component therapies that often contain combinations of non-specific agents [6]. The need to expand the scope of target-based therapies has resulted in development of compounds that affect more than one specific target [7], [8]. In this report, we explore the pharmacological properties of (R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF], a bitopic compound that acts as an antagonist of GPR55 receptor [9], [10] and an agonist of β2-adrenergic receptor (β2AR) [11]. Both are important tumor targets.