# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 1 Introduction
### Receptors  
Orexins A and B exert their functions throughout receptors type 1 (OXR1) and 2 (OXR2), which are G-protein-coupled receptors with seven transmembrane domains [13; 18; 26] belonging to the large class A rhodopsin-like subfamily of G-protein-coupled receptors [30]. OXR1 is encoded by the _hctrl_ gene located on chromosome 1, and OXR2 is encoded by the _hctrl_ gene located on chromosome 6 [25; 26]. The two receptors shared 64% of identity sequence [31] and can bind orexin A with the same affinity, and orexin B shows a better affinity for OXR2 than for OXR1 [3]. The identification of OXR2, but not OXR1, in non-mammals suggests that OXR2 could be the ancestral receptor form [21; 32]. The two orexin receptors lead to signal transduction by activation and/or inhibition of different intracellular signaling pathways to obtain final cellular responses [33]. The binding of ligands to their respective receptors induces a structural conformational change and the activation of G proteins [34]. At least three G-protein families can couple to both orexin receptors: G\({}_{\text{q}}\), G\({}_{\text{i/o}}\), and G\({}_{\text{s}}\)[18]. Like other receptors coupled to G proteins, orexin receptors (OXRs) may be engaged in dimerization/oligomerization processes, leading to homomeric and heteromeric complexes; these latter might affect receptor trafficking, signaling, or pharmacology [35; 36]. For example, heterodimers between human OXR1 and the CB\({}_{1}\) cannabinoid receptor have been verified, but the physiological significance of these interactions has not been completely diluted [18]. OXRs did not show significant affinity for other peptides. The transmembrane domains 1, 3, and 5 and the amino terminus of the receptors account for the interaction with the orexin peptides, and the transmembrane domain 3 is critical for receptor interactions with small molecule antagonists [37]. OXRs and the families of G proteins coupled with them regulate non-selective cation channels, phospholipases, and adenylyl cyclase, as well as protein and lipid kinases, and plastic effects are observed in some cell types [18]. Both OXRs exhibit slow kinetics in their response to orexin binding [37] and are widely distributed throughout the central nervous system but show a more restricted expression in the peripheral nervous system. Although a certain degree of overlap has been observed, the two receptors display different distributions [13]. It is well known that OXRs regulate homeostatic processes [38; 39; 40; 41; 42]. The most significant effect of orexin upon cells is the depolarization of neurons leading to increasing excitability and firing rate [43; 44; 45; 46], and this depolarization is produced by the activation of a non-selective cation current [18]. Although the mechanisms underlying OXR signaling in the central nervous system are mostly unknown, orexin responses in neurons include the modulation of presynaptic transmitter release and changes in synaptic plasticity [47; 48; 49; 50]. In experimental animals it has been described that the absence of one or both OXRs affects the markers of cholinergic transmission [51; 52]. In addition, the participation of the orexigenic system in human diseases (e.g., narcolepsy, obesity, drug addiction) has been reported [38; 40; 41]. It has been reported that the regulatory phosphorylation site (Ser-262) on the OXR1 did not affect its interaction with beta-arrestin1/2, G proteins or GRK (G-protein-coupled receptor kinase) 5 but abolished its interaction with GRK2 [53]. This means that Ser-262 is involved in the internalization of OXR1 and in promoting a GRK2-dependent biased signaling through orexin A. Moreover, the biased signaling between beta-arrestin/G protein is a promising strategy to improve drug efficacy [53]. It has been suggested that OXR1-selective antagonists might be potential anti-addiction drugs, but the role of OXR2 in drug seeking has not been established.