Orexin/hypocretin receptor signalling cascades

British Journal of Pharmacology

Volumn 171, Issue 2, 2014, Pages 314-331

  Kukkonen, J P ^a   Leonard, C S ^b  

^a UNIVERSITY OF HELSINKI   (Finland)

^b NEW YORK MEDICAL COLLEGE   (United States)

Author keywords

adenylyl cyclase; cell death; endocannabinoid; G protein coupled receptor; intracellular Ca 2+; K + channel; Na + K + exchanger; non selective cation channel; phospholipase; plasticity

Indexed keywords

ADENYLATE CYCLASE; BETA ARRESTIN; CALCIUM ION; ENDOCANNABINOID; G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; NEUROTRANSMITTER; OREXIN 1 RECEPTOR; OREXIN RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOLIPASE A2; PHOSPHOLIPASE C; PHOSPHOLIPASE D; POTASSIUM CHANNEL;

BINDING AFFINITY; CALCIUM SIGNALING; CALCIUM TRANSPORT; CELL DEATH; ENZYME ACTIVATION; ENZYME ACTIVITY; HUMAN; NERVE CELL MEMBRANE STEADY POTENTIAL; NERVE CELL PLASTICITY; NERVE STIMULATION; NEUROMODULATION; NEUROTRANSMITTER RELEASE; NONHUMAN; POSTSYNAPTIC INHIBITION; PRESYNAPTIC MEMBRANE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; SODIUM CALCIUM EXCHANGE;

ADENYLYL CYCLASE; CELL DEATH; ENDOCANNABINOID; G-PROTEIN-COUPLED RECEPTOR; INTRACELLULAR CA2+; K+ CHANNEL; NA+/K+ EXCHANGER; NON-SELECTIVE CATION CHANNEL; PHOSPHOLIPASE; PLASTICITY;

AMINO ACID SEQUENCE; ANIMALS; CELL DEATH; ENDOCANNABINOIDS; GTP-BINDING PROTEINS; HUMANS; MOLECULAR SEQUENCE DATA; NEURONAL PLASTICITY; OREXIN RECEPTORS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; SYNAPSES;

EID: 84891278490     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12324     Document Type: Review

References (145)

1. Acuna-Goycolea C, van den Pol AN, (2009). Neuroendocrine proopiomelanocortin neurons are excited by hypocretin/orexin. J Neurosci 29: 1503-1513.
2. Alexander SPH, et al. (2013). The Concise Guide to PHARMACOLOGY 2013/14: Overview. Br J Pharmacol 170: 1449-1867.
3. Ammoun S, Johansson L, Åkerman KEO, Korhonen L, Lindholm D, Kukkonen JP, (2003). Regulation of MAP/SAP-kinase cascades by orexin receptors. Neuroscience 2003. New Orleans, LA. Society for Neuroscience: Washington, DC. Program No. 161.14.
4. 2+ influx in OX1 receptor signaling. Mol Endocrinol 20: 80-99. (Pubitemid 43011672)
5. Ammoun S, Lindholm D, Wootz H, Åkerman KE, Kukkonen JP, (2006b). G-protein-coupled OX1 orexin/hcrtr-1 hypocretin receptors induce caspase-dependent and -independent cell death through p38 mitogen-/stress- activated protein kinase. J Biol Chem 281: 834-842.
6. Balsinde J, Balboa MA, (2005). Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal 17: 1052-1062. (Pubitemid 40933526)
7. Bernard R, Lydic R, Baghdoyan HA, (2002). Hypocretin-1 activates G proteins in arousal-related brainstem nuclei of rat. Neuroreport 13: 447-450. (Pubitemid 34293187)
8. Bernard R, Lydic R, Baghdoyan HA, (2003). Hypocretin-1 causes G protein activation and increases ACh release in rat pons. Eur J Neurosci 18: 1775-1785. (Pubitemid 37372362)
9. Borgland SL, (2013). Orexin system as a mediator of addiction & compulsion. Br J Pharmacol (in press).
10. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A, (2006). Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49: 589-601. (Pubitemid 43221893)
11. Borgland SL, Storm E, Bonci A, (2008). Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 28: 1545-1556.
12. Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N, Floresco SB, et al. (2009). Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 29: 11215-11225.
13. Brown DA, (2010). Muscarinic acetylcholine receptors (mAChRs) in the nervous system: some functions and mechanisms. J Mol Neurosci 41: 340-346.
14. Brown RE, Sergeeva OA, Eriksson KS, Haas HL, (2002). Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 22: 8850-8859. (Pubitemid 35379054)
15. Bulenger S, Marullo S, Bouvier M, (2005). Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci 26: 131-137. (Pubitemid 40313592)
16. Burdakov D, Liss B, Ashcroft FM, (2003). Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium-calcium exchanger. J Neurosci 23: 4951-4957. (Pubitemid 36793221)
17. Burlet S, Tyler CJ, Leonard CS, (2002). Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 22: 2862-2872. (Pubitemid 37465835)
18. Chen X, Talley EM, Patel N, Gomis A, McIntire WE, Dong B, et al. (2006). Inhibition of a background potassium channel by Gq protein alpha-subunits. Proc Natl Acad Sci U S A 103: 3422-3427. (Pubitemid 43346484)
19. Davis SF, Williams KW, Xu W, Glatzer NR, Smith BN, (2003). Selective enhancement of synaptic inhibition by hypocretin (orexin) in rat vagal motor neurons: implications for autonomic regulation. J Neurosci 23: 3844-3854. (Pubitemid 36958491)
20. Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G, (2011). Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111: 6130-6185.
21. Dergacheva O, Bateman R, Byrne P, Mendelowitz D, (2012). Orexinergic modulation of GABAergic neurotransmission to cardiac vagal neurons in the brain stem nucleus ambiguus changes during development. Neuroscience 209: 12-20.
22. + conductances contribute to resting membrane potential and to orexin-induced membrane depolarization in rat thalamic paraventricular nucleus neurons. Neuroscience 158: 1560-1570.
23. Duguay D, Belanger-Nelson E, Mongrain V, Beben A, Khatchadourian A, Cermakian N, (2011). Dynein light chain Tctex-type 1 modulates orexin signaling through its interaction with orexin 1 receptor. PLoS ONE 6: e26430.
24. Ekholm ME, Johansson L, Kukkonen JP, (2007). IP(3)-independent signalling of OX(1) orexin/hypocretin receptors to Ca(2+) influx and ERK. Biochem Biophys Res Commun 353: 475-480. (Pubitemid 46014588)
25. Ekholm ME, Johansson L, Kukkonen JP, (2010). Rapid and easy semi-quantitative evaluation method for diacylglycerol and inositol-1,4,5- trisphosphate generation in orexin receptor signalling. Acta Physiol (Oxf) 198: 387-392.
26. El Firar A, Voisin T, Rouyer-Fessard C, Ostuni MA, Couvineau A, Laburthe M, (2009). Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis. FASEB J 23: 4069-4080.
27. Ellis J, Pediani JD, Canals M, Milasta S, Milligan G, (2006). Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. J Biol Chem 281: 38812-38824. (Pubitemid 46042008)
28. Eriksson KS, Sergeeva O, Brown RE, Haas HL, (2001). Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 21: 9273-9279. (Pubitemid 33096871)
29. Evans NA, Groarke DA, Warrack J, Greenwood CJ, Dodgson K, Milligan G, et al. (2001). Visualizing differences in ligand-induced beta-arrestin-GFP interactions and trafficking between three recently characterized G protein-coupled receptors. J Neurochem 77: 476-485. (Pubitemid 32298742)
30. Gamper N, Shapiro MS, (2007). Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci 8: 921-934. (Pubitemid 350146933)
31. 2+ signaling. Cold Spring Harb Perspect Biol 2: a003962.
32. Göncz E, Strowski MZ, Grotzinger C, Nowak KW, Kaczmarek P, Sassek M, et al. (2008). Orexin-A inhibits glucagon secretion and gene expression through a Foxo1-dependent pathway. Endocrinology 149: 1618-1626. (Pubitemid 351468335)
33. Haj-Dahmane S, Shen RY, (2005). The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci 25: 896-905. (Pubitemid 40171005)
34. Hilairet S, Bouaboula M, Carriere D, Le Fur G, Casellas P, (2003). Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 278: 23731-23737. (Pubitemid 36830197)
35. Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, et al. (2011). Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)- induced disinhibition. J Neurosci 31: 14600-14610.
36. Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y, (2003). Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 90: 693-702. (Pubitemid 37092554)
37. + channels in cultured nucleus basalis neurons. J Neurophysiol 92: 3183-3191. (Pubitemid 39506297)
38. Holmqvist T, Åkerman KEO, Kukkonen JP, (2002). Orexin signaling in recombinant neuron-like cells. FEBS Lett 526: 11-14. (Pubitemid 35245683)
39. Holmqvist T, Johansson L, Östman M, Ammoun S, Åkerman KE, Kukkonen JP, (2005). OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms. J Biol Chem 280: 6570-6579. (Pubitemid 40341207)
40. Ishibashi M, Takano S, Yanagida H, Takatsuna M, Nakajima K, Oomura Y, et al. (2005). Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro. Peptides 26: 471-481. (Pubitemid 40126704)
41. Jäntti MH, Putula J, Somerharju P, Frohman MA, Kukkonen JP, (2012). OX(1) orexin/hypocretin receptor activation of phospholipase D. Br J Pharmacol 165: 1109-1123.
42. Jäntti MH, Putula J, Turunen PM, Näsman J, Reijonen S, Kukkonen JP, (2013). Autocrine endocannabinoid signaling potentiates orexin receptor signaling upon CB1 cannabinoid-OX1 orexin receptor coexpression. Mol Pharmacol 83: 621-632.
43. Johansson L, Ekholm ME, Kukkonen JP, (2007). Regulation of OX(1) orexin/hypocretin receptor-coupling to phospholipase C by Ca(2+) influx. Br J Pharmacol 150: 97-104. (Pubitemid 46094674)
44. Johansson L, Ekholm ME, Kukkonen JP, (2008). Multiple phospholipase activation by OX(1) orexin/hypocretin receptors. Cell Mol Life Sci 65: 1948-1956.
45. Kalogiannis M, Grupke SL, Potter PE, Edwards JG, Chemelli RM, Kisanuki YY, et al. (2010). Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons. Eur J Neurosci 32: 130-142.
46. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M, (2009). Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89: 309-380.
47. Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW, (2001). Expression and coupling characteristics of the crh and orexin type 2 receptors in human fetal adrenals. J Clin Endocrinol Metab 86: 4512-4519. (Pubitemid 32848582)
48. Karteris E, Chen J, Randeva HS, (2004). Expression of human prepro-orexin and signaling characteristics of orexin receptors in the male reproductive system. J Clin Endocrinol Metab 89: 1957-1962. (Pubitemid 38507957)
49. Karteris E, Machado RJ, Chen J, Zervou S, Hillhouse EW, Randeva HS, (2005). Food deprivation differentially modulates orexin receptor expression and signalling in the rat hypothalamus and adrenal cortex. Am J Physiol Endocrinol Metab 288: E1089-E1100. (Pubitemid 40726795)
50. Kilduff TS, Bowersox SS, Kaitin KI, Baker TL, Ciaranello RD, Dement WC, (1986). Muscarinic cholinergic receptors and the canine model of narcolepsy. Sleep 9: 102-106. (Pubitemid 18008479)
51. 2+ channels in GH3 cells via a specific G(o) splice variant. Ciba Found Symp 190: 171-182. discussion 182-176.
52. Kohlmeier KA, Inoue T, Leonard CS, (2004). Hypocretin/orexin peptide signalling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol 92: 221-235. (Pubitemid 38802246)
53. 2+ transients mediated by L-type calcium channels. J Neurophysiol 100: 2265-2281.
54. 2+ signals. Semin Cell Dev Biol 23: 172-180.
55. Korotkova TM, Eriksson KS, Haas HL, Brown RE, (2002). Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul Pept 104: 83-89. (Pubitemid 34119377)
56. 2+ exchange inhibitor KB-R7943 potently blocks TRPC channels. Biochem Biophys Res Commun 361: 230-236. (Pubitemid 47102290)
57. Kukkonen JP, (2004). Regulation of receptor-coupling to (multiple) G-proteins. A challenge for basic research and drug discovery. Receptors Channels 10: 167-183. (Pubitemid 40778697)
58. Kukkonen JP, (2011). A ménage à trois made in heaven: G-protein-coupled receptors, lipids and TRP channels. Cell Calcium 50: 9-26.
59. Kukkonen JP, (2013a). Lipid signaling cascades of orexin/hypocretin receptors. Biochimie doi: 10.1016/j.biochi.2013.06.015.
60. Kukkonen JP, (2013b). Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am J Physiol Cell Physiol 301: C2-C32.
61. 2+ channels. Neuroreport 12: 2017-2020. (Pubitemid 32553724)
62. Laitinen JT, (2004). [35S]GTPgS autoradiography: a powerful functional approach with expanding potential for neuropharmacological studies on receptors coupled to Gi family of G proteins. Current Neuropharmacol 2: 191-206. (Pubitemid 38854953)
63. Lambe EK, Aghajanian GK, (2003). Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron 40: 139-150. (Pubitemid 37222469)
64. 2+-dependent mechanism. Biochem Biophys Res Commun 309: 209-216.
65. 2+ entry: evidence for involvement of TRPC channels and protein kinase C regulation. J Biol Chem 280: 1771-1781.
66. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: 322-327. (Pubitemid 28103952)
67. Leonard CS, Kukkonen JP, (2013). Orexin/hypocretin receptor signalling: a functional perspective. Br J Pharmacol 171: 294-313.
68. Li H, de Lecea L, (2013). The orexins as integrators of multiple physiological functions. Br J Pharmacol 171: 332-350.
69. Li Y, Gao XB, Sakurai T, van den Pol AN, (2002). Hypocretin/orexin excites hypocretin neurons via a local glutamate neuron-a potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36: 1169-1181. (Pubitemid 36044516)
70. Lindner M, Leitner MG, Halaszovich CR, Hammond GR, Oliver D, (2011). Probing the regulation of TASK potassium channels by PI4,5P(2) with switchable phosphoinositide phosphatases. J Physiol 589: 3149-3162.
71. Liu RJ, van den Pol AN, Aghajanian GK, (2002). Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 22: 9453-9464. (Pubitemid 35356188)
72. Louhivuori LM, Jansson L, Nordstrom T, Bart G, Nasman J, Akerman KE, (2010). Selective interference with TRPC3/6 channels disrupts OX1 receptor signalling via NCX and reveals a distinct calcium influx pathway. Cell Calcium 48: 114-123.
73. 2+ influx pathway necessary for coupling to phospholipase C. J Biol Chem 275: 30806-30812.
74. Luscher C, Slesinger PA, (2010). Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 11: 301-315.
75. 2+ transport. Biochem J 406: 365-382. (Pubitemid 47425443)
76. 2+ signalling by the orexin receptor type 1. Biochem Pharmacol 71: 827-836. (Pubitemid 43208839)
77. Malendowicz LK, Tortorella C, Nussdorfer GG, (1999). Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade. J Steroid Biochem Mol Biol 70: 185-188. (Pubitemid 29528428)
78. Mangmool S, Kurose H, (2011). G(i/o) protein-dependent and -independent actions of pertussis toxin (PTX). Toxins (Basel) 3: 884-899.
79. Mathie A, (2007). Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J Physiol 578: 377-385. (Pubitemid 46092203)
80. Mazzocchi G, Malendowicz LK, Aragona F, Rebuffat P, Gottardo L, Nussdorfer GG, (2001a). Human pheochromocytomas express orexin receptor type 2 gene and display an in vitro secretory response to orexins A and B. J Clin Endocrinol Metab 86: 4818-4821. (Pubitemid 33020526)
81. Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG, (2001b). Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J Clin Endocrinol Metab 86: 778-782. (Pubitemid 32207496)
82. Milasta S, Evans NA, Ormiston L, Wilson S, Lefkowitz RJ, Milligan G, (2005). The sustainability of interactions between the orexin-1 receptor and beta-arrestin-2 is defined by a single C-terminal cluster of hydroxy amino acids and modulates the kinetics of ERK MAPK regulation. Biochem J 387: 573-584. (Pubitemid 40685690)
83. Milligan G, (2009). G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 158: 5-14.
84. Monovich L, Mugrage B, Quadros E, Toscano K, Tommasi R, LaVoie S, et al. (2007). Optimization of halopemide for phospholipase D2 inhibition. Bioorg Med Chem Lett 17: 2310-2311. (Pubitemid 46484301)
85. 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19: 1524-1534. (Pubitemid 38437915)
86. 2+ entry via diacylglycerol-activated channels in differentiated neuroblastoma cells. J Neurosci 26: 10658-10666.
87. Newton AC, (2010). Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab 298: E395-E402.
88. Nilius B, Owsianik G, Voets T, Peters JA, (2007). Transient receptor potential cation channels in disease. Physiol Rev 87: 165-217. (Pubitemid 46207713)
89. Ono K, Kai A, Honda E, Inenaga K, (2008). Hypocretin-1/orexin-A activates subfornical organ neurons of rats. Neuroreport 19: 69-73. (Pubitemid 351339623)
90. Ono T, Yamada K, Chikazawa Y, Ueno M, Nakamoto S, Okuno T, et al. (2002). Characterization of a novel inhibitor of cytosolic phospholipase A2alpha, pyrrophenone. Biochem J 363: 727-735. (Pubitemid 34526393)
91. Peltonen HM, Magga JM, Bart G, Turunen PM, Antikainen MS, Kukkonen JP, et al. (2009). Involvement of TRPC3 channels in calcium oscillations mediated by OX(1) orexin receptors. Biochem Biophys Res Commun 385: 408-412.
92. Peltonen HM, Åkerman KE, Bart G, (2010). A role for PKD1 and PKD3 activation in modulation of calcium oscillations induced by orexin receptor 1 stimulation. Biochim Biophys Acta 1803: 1206-1212.
93. van den Pol AN, (1999). Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19: 3171-3182. (Pubitemid 29174009)
94. van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB, (1998). Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 18: 7962-7971. (Pubitemid 28441034)
95. van den Pol AN, Patrylo PR, Ghosh PK, Gao XB, (2001). Lateral hypothalamus: early developmental expression and response to hypocretin (orexin). J Comp Neurol 433: 349-363. (Pubitemid 32280656)
96. Putula J, Kukkonen JP, (2012). Mapping of the binding sites for the OX(1) orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras. Neurosci Lett 506: 111-115.
97. Putula J, Turunen PM, Jäntti MH, Ekholm ME, Kukkonen JP, (2011). Agonist ligand discrimination by the two orexin receptors depends on the expression system. Neurosci Lett 494: 57-60.
98. Rajagopal S, Rajagopal K, Lefkowitz RJ, (2010). Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9: 373-386.
99. Ramanjaneya M, Conner AC, Chen J, Stanfield PR, Randeva HS, (2008). Orexins stimulate steroidogenic acute regulatory protein expression through multiple signaling pathways in human adrenal H295R cells. Endocrinology 149: 4106-4115.
100. Ramanjaneya M, Conner AC, Chen J, Kumar P, Brown JE, Johren O, et al. (2009). Orexin-stimulated MAP kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: diverse roles for orexins A and B. J Endocrinol 202: 249-261.
101. Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW, (2001). Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. J Clin Endocrinol Metab 86: 4808-4813. (Pubitemid 33020524)
102. Ritter SL, Hall RA, (2009). Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10: 819-830.
103. Rouet-Benzineb P, Rouyer-Fessard C, Jarry A, Avondo V, Pouzet C, Yanagisawa M, et al. (2004). Orexins acting at native OX(1) receptor in colon cancer and neuroblastoma cells or at recombinant OX(1) receptor suppress cell growth by inducing apoptosis. J Biol Chem 279: 45875-45886. (Pubitemid 39491580)
104. Rozengurt E, (2007). Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol 213: 589-602. (Pubitemid 350058250)
105. Sadja R, Alagem N, Reuveny E, (2003). Gating of GIRK channels: details of an intricate, membrane-delimited signaling complex. Neuron 39: 9-12. (Pubitemid 36830944)
106. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573-585. (Pubitemid 28101119)
107. Schneider OD, Weiss AA, Miller WE, (2007). Pertussis toxin utilizes proximal components of the T-cell receptor complex to initiate signal transduction events in T cells. Infect Immun 75: 4040-4049. (Pubitemid 47206303)
108. Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, et al. (2009). Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol 5: 108-117.
109. Selbach O, Doreulee N, Bohla C, Eriksson KS, Sergeeva OA, Poelchen W, et al. (2004). Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling. Neuroscience 127: 519-528. (Pubitemid 38950665)
110. Selbach O, Bohla C, Barbara A, Doreulee N, Eriksson KS, Sergeeva OA, et al. (2010). Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases. Acta Physiol (Oxf) 198: 277-285.
111. Sellayah D, Bharaj P, Sikder D, (2011). Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 14: 478-490.
112. Shenoy SK, Lefkowitz RJ, (2011). β-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32: 521-533.
113. Shin HS, Cho HS, Sung KW, Yoon BJ, (2009). Orexin-A increases cell surface expression of AMPA receptors in the striatum. Biochem Biophys Res Commun 378: 409-413.
114. Shuttleworth TJ, (2009). Arachidonic acid, ARC channels, and Orai proteins. Cell Calcium 45: 602-610.
115. Skrzypski M, Le TT, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D, et al. (2011). Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes. Diabetologia 54: 1841-1852.
116. Skrzypski M, Kaczmarek P, Le TT, Wojciechowicz T, Pruszynska-Oszmalek E, Szczepankiewicz D, et al. (2012). Effects of orexin A on proliferation, survival, apoptosis and differentiation of 3T3-L1 preadipocytes into mature adipocytes. FEBS Lett 586: 4157-4164.
117. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. (1999). Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br J Pharmacol 128: 1-3. (Pubitemid 29425260)
118. Smith BN, Davis SF, Van Den Pol AN, Xu W, (2002). Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 115: 707-714. (Pubitemid 35336013)
119. Squecco R, Garella R, Luciani G, Francini F, Baccari MC, (2011). Muscular effects of orexin A on the mouse duodenum: mechanical and electrophysiological studies. J Physiol 589: 5231-5246.
120. Su W, Yeku O, Olepu S, Genna A, Park JS, Ren H, et al. (2009). 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol Pharmacol 75: 437-446.
121. Suh BC, Hille B, (2008). PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys 37: 175-195.
122. Sunahara RK, Taussig R, (2002). Isoforms of mammalian adenylyl cyclase: multiplicities of signaling. Mol Interv 2: 168-184.
123. Tang J, Chen J, Ramanjaneya M, Punn A, Conner AC, Randeva HS, (2008). The signalling profile of recombinant human orexin-2 receptor. Cell Signal 20: 1651-1661.
124. 2+ signalling: problems and pitfalls. Trends Pharmacol Sci 19: 370-375. (Pubitemid 28458834)
125. Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, et al. (2005). Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci 25: 7459-7469. (Pubitemid 41129819)
126. Turunen PM, Ekholm ME, Somerharju P, Kukkonen JP, (2010). Arachidonic acid release mediated by OX(1) orexin receptors. Br J Pharmacol 159: 212-221.
127. Turunen PM, Jäntti MH, Kukkonen JP, (2012). OX1 orexin/hypocretin receptor signaling via arachidonic acid and endocannabinoid release. Mol Pharmacol 82: 156-167.
128. 2+ signaling in dopamine neurons of the ventral tegmental area. Neuroreport 12: 1885-1889. (Pubitemid 32553702)
129. Venkatachalam K, Montell C, (2007). TRP channels. Annu Rev Biochem 76: 387-417.
130. Voisin T, Firar AE, Avondo V, Laburthe M, (2006). Orexin-induced apoptosis: the key role of the seven-transmembrane domain orexin type 2 receptor. Endocrinology 147: 4977-4984. (Pubitemid 44402205)
131. Voisin T, El Firar A, Rouyer-Fessard C, Gratio V, Laburthe M, (2008). A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism. FASEB J 22: 1993-2002. (Pubitemid 351811475)
132. Voisin T, El Firar A, Fasseu M, Rouyer-Fessard C, Descatoire V, Walker F, et al. (2011). Aberrant expression of OX1 receptors for orexins in colon cancers and liver metastases: an openable gate to apoptosis. Cancer Res 71: 3341-3351.
133. Ward RJ, Pediani JD, Milligan G, (2011a). Hetero-multimerization of the cannabinoid CB1 receptor and the orexin OX1 receptor generates a unique complex in which both protomers are regulated by orexin A. J Biol Chem 286: 37414-37428.
134. Ward RJ, Pediani JD, Milligan G, (2011b). Ligand-induced internalization of the orexin OX(1) and cannabinoid CB(1) receptors assessed via N-terminal SNAP and CLIP-tagging. Br J Pharmacol 162: 1439-1452.
135. Wenzel J, Grabinski N, Knopp CA, Dendorfer A, Ramanjaneya M, Randeva HS, et al. (2009). Hypocretin/orexin increases the expression of steroidogenic enzymes in human adrenocortical NCI H295R cells. Am J Physiol Regul Integr Comp Physiol 297: R1601-R1609.
136. Winrow CJ, Renger JJ, (2013). Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 171: 283-293.
137. Wu M, Zhang Z, Leranth C, Xu C, van den Pol AN, Alreja M, (2002). Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition. J Neurosci 22: 7754-7765. (Pubitemid 35386374)
138. Wu M, Zaborszky L, Hajszan T, van den Pol AN, Alreja M, (2004). Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons. J Neurosci 24: 3527-3536. (Pubitemid 38481109)
139. Wymann MP, Zvelebil M, Laffargue M, (2003). Phosphoinositide 3-kinase signalling-which way to target? Trends Pharmacol Sci 24: 366-376. (Pubitemid 37315529)
140. Xu R, Wang Q, Yan M, Hernandez M, Gong C, Boon WC, et al. (2002). Orexin-A augments voltage-gated Ca(2+) currents and synergistically increases growth hormone (GH) secretion with GH-releasing hormone in primary cultured ovine somatotropes. Endocrinology 143: 4609-4619. (Pubitemid 35397602)
141. Xu TR, Ward RJ, Pediani JD, Milligan G, (2011). The orexin OX1 receptor exists predominantly as a homodimer in the basal state: potential regulation of receptor organization by both agonist and antagonist ligands. Biochem J 439: 171-183.
142. Yang B, Samson WK, Ferguson AV, (2003). Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci 23: 6215-6222. (Pubitemid 36875622)
143. Yuan JP, Lee KP, Hong JH, Muallem S, (2012). The closing and opening of TRPC channels by Homer1 and STIM1. Acta Physiol (Oxf) 204: 238-247.
144. Zhang J, Li B, Yu L, He YC, Li HZ, Zhu JN, et al. (2011). A role for orexin in central vestibular motor control. Neuron 69: 793-804.
145. + conductances contribute to a slow AHP in thalamic paraventricular nucleus neurons: a novel target for orexin receptors. J Neurophysiol 104: 2052-2062.