Fig. (1).

Schematic depiction of hypocretin/orexin system. Hypocretin-1/Orexin A (Hcrt-1/OrxA) and hypocretin-2/Orexin B (Hcrt-2/OrxB) are derived from a common precursor peptide, pre-pro-hypocretin. After removal of the N-terminal secretory signal sequence, pre-prohypocretin is cleaved at specific sites having basic amino acid residues to yield the two mature peptides. Hcrt-1/OrxA possesses two disulfide bridges while Hcrt-2/OxB is linear. The actions of hypocretins are mediated through interaction with two heterotrimeric G protein-coupled receptors (Hcrt/Orx₁R and Hcrt/Orx₂R), whose distribution in the central nervous system is regionally specific. Hcrt/Orx₁R is more selective for Hcrt-1/OrxA, while Hcrt/Orx₂R is equally specific for both peptides. Hcrt-1/OrxA is linked exclusively to excitatory G proteins of the Gq subclass, whereas Hcrt-2/OxB couples in vitro to excitatory Gq and/or inhibitory Gi/o. Signaling through Gq pathway results in increase of intracellular Ca²⁺, most probably via activation of phospholipase C-b with subsequent triggering of the phosphatidylinositol cascade and activation of protein kinase C. The Ca²⁺ influx likely induces depolarization. Signaling via inhibitory Gi/o pathway may occur through hyperpolarization due to K+ efflux (GIRK channel-mediated). Figure modified from [9].