The orexins, also known as hypocretins, are a pair of neuropeptides that are mainly derived from orexin-containing neurons in the lateral hypothalamus (LH). Orexin-A (OA; hypocretin-1) and orexin-B (OB; hypocretin-2) are closely related small peptides that are widely distributed throughout the central and peripheral nervous systems. Orexins stimulate food intake upon intracerebroventricular administration, and were originally described as regulators of feeding behavior. Subsequent experiments revealed many other important physiological functions of these peptides, including regulation of the sleep–wake cycle, energy homeostasis (Tsuneki et al., 2012), neuroendocrine functions, glucose metabolism, stress-adaptive responses and reward-seeking and drug addiction.
Orexins bind their cognate G-protein–coupled receptors (GPCRs), orexin receptor type 1 (OX1R, also named as Hcrtr-1) and type 2 (OX2R, or Hcrtr-2), which activate different downstream signal pathways, thereby exerting a variety of physiological functions. Orexin and orexin receptors are ectopically expressed in many diseases, especially neurological disorders, suggesting that the orexin/receptor pathway plays critical roles in the pathology and pathogenesis of these illnesses. OA and OB orchestrate their diverse effects by binding and activating two GPCRs, OX1R and OX2R. The mRNAs of human OX1R and OX2R are 1564 and 1843 bp in length, respectively, and are translated into proteins of 425 and 444 aa. OX1R and OX2R share 64% amino acid identity. Rat OX1R and OX2R mRNAs are 2469 and 3114 bp in length, respectively, and encode proteins of 413 and 460 aa. Human and rat OX1R and OX2R share 94% and 95% identity, indicating that the orexin receptor is highly conserved among mammals. 
Calcium is a very important second messenger of GPCR-mediated signaling. Previous studies demonstrated that orexin treatment significantly increases the intracellular Ca2+ concentration ([Ca2+]i) in cells overexpressing OX1R and OX2R, an effect that is mainly triggered by activation of the classical phospholipase C (PLC) cascade (PLC-IP3/DAG). Subsequent work showed that OA acts on OX1R, which in turn activates transient receptor potential channel 3 (TRPC3), thereby triggering Ca2+ responses.Other orexin/receptor signaling pathways have also been reported, including the phospholipase D (PLD)/phosphatidic acid (PA), phospholipase A (PLA)/arachidonic acid (AA), and mitogen-activated protein kinase (MAPK) cascades. Orexins also activate p38-MAPK signaling pathway and increase the level of phosphorylated ERK1/2 in a dose- and time-dependent manner in both cell lines and tissues. ERK1/2 activation induced by orexins involves Gq/PLC/PKC signaling, but not the PKA pathway. In addition, OA affects rat insulinoma cell proliferation via stimulation of the AKT signaling pathway by OX1R.

References

1.Wang C, et al. Front Mol Neurosci. 2018;11:220.