Orexin Receptors

The orexins (hypocretins) are a newly discovered family of neuropeptides which play a role in regulating feeding and wakefulness. The family currently consists of two members; orexin A and orexin B (33- and 28-residues respectively), which are produced from a common precursor prepro-orexin (130 amino acids). Cell bodies of orexin-containing neurons are largely confined to the lateral hypothalamus, an area classically linked to feeding stimulation. Intracerebroventricular injections of orexin A and orexin B stimulate feeding in a dose-related manner, with orexin A being significantly more effective than orexin B. Orexins are also strongly linked to the regulation of sleep-activity cycles, which may restrict the use of orexin ligands in the treatment of obesity. The orexins activate two G-protein-coupled receptors (OX₁ and OX₂) also found predominantly in the hypothalamus. Orexin A is the selective endogenous agonist for OX₁ and blocking this receptor modulates food and water intake.

Receptor Subtype	OX₁ Receptors	OX₂ Receptors

G protein	G_q/11	G_q/11
Transduction Mechanism	↑ PLC → ↑ Ca²⁺ influx	↑ PLC → ↑ Ca²⁺ influx
Primary Locations	Ventromedial hypothalamus, locus coeruleus, median raphe, hippocampus, tenia tecta	Cerebral cortex (layers IV-VI), medial hypothalamus, paraventricular hypothalamus, nucleus accumbens, subthalamic and paraventricular thalamus, anterior pretectal nucleus
Likely Physiological Roles	Sleep-wakefulness, energy homeostasis	Sleep-wakefulness

Key Compounds	K_i Values (nM)

Orexin A (human, rat, mouse) (1455)	20	38
Orexin B (human) (1456)	420	36
SB 334867 (1960)	7.2*	< 5*
SB 408124 (1963)	21.7^†	1405^†
[Ala¹¹,D-Leu¹⁵-Orexin B (2142)	52^‡	0.13^‡

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Written by T. Kenakin et al

'Seven Transmembrane Receptor Signaling' highlights the multiple behaviors of 7-TMs including G-protein-dependent and -independent signaling as well as the concept of collateral efficacy