Functions of the orexinergic/hypocretinergic system

Abstract

Orexin A and orexin B are hypothalamic peptides that act on their targets via two G protein-coupled receptors (OX1 and OX2 receptors). In the central nervous system, the cell bodies producing orexins are localized in a narrow region within the lateral hypothalamus and project mainly to regions involved in feeding, sleep, and autonomic functions. Via putative pre- and postsynaptic effects, orexins increase synaptic activity in these regions. In isolated neurons and cells expressing recombinant receptors orexins cause Ca2+ elevation, which is mainly dependent on influx. The activity of orexinergic cells appears to be controlled by feeding- and sleep-related signals via a variety of neurotransmitters/hormones from the brain and other tissues. Orexins and orexin receptors are also found outside the central nervous system, particularly in organs involved in feeding and energy metabolism, e.g., gastrointestinal tract, pancreas, and adrenal gland. In the present review we focus on the physiological properties of the cells that secrete or respond to orexins.

Nociception and autonomic nervous system

“…The thalamic areas receiving visceral inputs from the PBN is adjacent to that receiving nociceptive and thermoceptive spinothalamic and trigemino-thalamic pathways. The posterior hypothalamus (Hypocr/Orxs neurons) and the paraventricular nucleus are sites of integration of trigeminal, visceral, environmental, and circadian information and are involved in the integration of autonomic, antinociceptive, and pain modulatory responses [73]. The insula is the primary viscerosensory cortex and is also the primary cortical area receiving pain and temperature informations.…”

The Orexin OX1Receptor Regulates Ca2+Entry via Diacylglycerol-Activated Channels in Differentiated Neuroblastoma Cells

“…Evidence for orexin involvement in arousal and sleep/wake regulation has come from studies on animals with disrupted or modified orexin signaling system (Chemelli et al, 1999;Lin et al, 1999;Hara et al, 2001), which in some cases leads to the sleeping disorder narcolepsy. Orexins are also implicated in other physiological functions, such as regulation of food intake and metabolic processes and neuroendocrine functions (for review, see Kukkonen et al, 2002).…”

“…Orexins excite neurons by activating either or both of two identified G-protein-coupled orexin receptors, OX 1 R and OX 2 R (Sakurai et al, 1998). Investigations of the intracellular mechanisms for excitation have generated several plausible signaling pathways (for review, see Kukkonen et al, 2002;Ferguson and Samson, 2003). A useful indicator for OXR activation is an increase in intracellular Ca 2ϩ concentration, [Ca 2ϩ ] i .…”

Orexin/hypocretin receptor chimaeras reveal structural features important for orexin peptide distinction

“…In contrast, a point mutation Glu54Lys of OX 2 , also found in dog, shows proper membrane localization but a strongly reduced orexin-A binding and orexin-A and -B signaling [15]. Interestingly, this glutamate (and several other amino acids in its vicinity) is conserved also in OX 1 Abbreviations: A 11 ,DL 15 -orexin-B, Ala 11 , D-Leu 15 -orexin-B; C, C-terminus of orexin receptors; Ch1-8, chimaeric orexin receptors 1-8; EC1-3, extracellular loops of orexin receptor 1-3; GFP, green fluorescent protein; IC1-3, intracellular loops of orexin receptor 1-3; N, N-terminus of orexin receptors; TM1-7, transmembrane helices of orexin receptor [1][2][3][4][5][6][7] (Glu46). A number of single nucleotide polymorphisms of orexin receptors are known [6], but have not been consequently investigated.…”