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The Journal of Neuroscience, October 1, 1998, 18(19):7962-7971
Presynaptic and Postsynaptic Actions and Modulation of
Neuroendocrine Neurons by a New Hypothalamic Peptide,
Hypocretin/Orexin
Anthony N.
van den Pol1, 2,
Xiao-Bing
Gao1,
Karl
Obrietan2,
Thomas S.
Kilduff2, and
Andrei B.
Belousov2
1 Department of Neurosurgery, Yale University Medical
School, New Haven, Connecticut 06520, and 2 Department of
Biological Sciences, Stanford University, Stanford, California 94305
A new orexigenic peptide called hypocretin (orexin) has recently
been described in neurons of the lateral hypothalamus and perifornical
area. The medial and lateral hypothalamus have been loosely called
satiety and feeding centers of the brain, respectively. Approximately
one-third of all medial and lateral hypothalamic neurons tested, but
not hippocampal neurons, show a striking nanomolar sensitivity to
hypocretin. As studied with calcium digital imaging with fura-2,
hypocretin raises cytoplasmic calcium via a mechanism based on
G-protein enhancement of calcium influx through plasma membrane
channels. The peptide has a potent effect at both presynaptic and
postsynaptic receptors. Most synaptic activity in hypothalamic circuits
is attributable to axonal release of GABA or glutamate. With whole-cell
patch-clamp recording, we show that hypocretin, acting directly at axon
terminals, can increase the release of each of these amino acid
transmitters. Two hypocretin peptides, hypocretin-1 and hypocretin-2,
are coded by a single gene; neurons that respond to one peptide also
respond to the other. In addition to its effect on feeding, we find
that this peptide also regulates the synaptic activity of
physiologically identified neuroendocrine neurons studied in
hypothalamic slices containing the arcuate nucleus, suggesting a second
function of hypocretin in hormone regulation. The widespread
distribution of hypocretin axons, coupled with the strong response to
the peptide at both presynaptic and postsynaptic sites, suggests that
the peptide probably modulates a variety of hypothalamic regulatory
systems and could regulate the axonal input to these regions
presynaptically.
Key words:
hypothalamus; presynaptic; neuroendocrine; neuromodulation; neuropeptide; glutamate; GABA; feeding
Copyright © 1998 Society for Neuroscience 0270-6474/98/18197962-10$05.00/0
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Hypocretins (Orexins) Regulate Serotonin Neurons in the Dorsal Raphe Nucleus by Excitatory Direct and Inhibitory Indirect Actions
J. Neurosci.,
November 1, 2002;
22(21):
9453 - 9464.
[Abstract]
[Full Text]
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M. Wu, Z. Zhang, C. Leranth, C. Xu, A. N. van den Pol, and M. Alreja
Hypocretin Increases Impulse Flow in the Septohippocampal GABAergic Pathway: Implications for Arousal via a Mechanism of Hippocampal Disinhibition
J. Neurosci.,
September 1, 2002;
22(17):
7754 - 7765.
[Abstract]
[Full Text]
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L. I. Kiyashchenko, B. Y. Mileykovskiy, N. Maidment, H. A. Lam, M.-F. Wu, J. John, J. Peever, and J. M. Siegel
Release of Hypocretin (Orexin) during Waking and Sleep States
J. Neurosci.,
July 1, 2002;
22(13):
5282 - 5286.
[Abstract]
[Full Text]
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X.-B. Gao and A. N van den Pol
Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons
J. Physiol.,
July 1, 2002;
542(1):
273 - 286.
[Abstract]
[Full Text]
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M.-C. Xi, S. J. Fung, J. Yamuy, F. R. Morales, and M. H. Chase
Induction of Active (REM) Sleep and Motor Inhibition by Hypocretin in the Nucleus Pontis Oralis of the Cat
J Neurophysiol,
June 1, 2002;
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2880 - 2888.
[Abstract]
[Full Text]
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A. N van den Pol, P. K Ghosh, R.-j. Liu, Y. Li, G. K Aghajanian, and X.-B. Gao
Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus
J. Physiol.,
May 15, 2002;
541(1):
169 - 185.
[Abstract]
[Full Text]
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S. Burlet, C. J. Tyler, and C. S. Leonard
Direct and Indirect Excitation of Laterodorsal Tegmental Neurons by Hypocretin/Orexin Peptides: Implications for Wakefulness and Narcolepsy
J. Neurosci.,
April 1, 2002;
22(7):
2862 - 2872.
[Abstract]
[Full Text]
[PDF]
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I O Ebrahim, R S Howard, M D Kopelman, M K Sharief, and A J Williams
The hypocretin/orexin system
J R Soc Med,
January 5, 2002;
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[Full Text]
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K. S. Eriksson, O. Sergeeva, R. E. Brown, and H. L. Haas
Orexin/Hypocretin Excites the Histaminergic Neurons of the Tuberomammillary Nucleus
J. Neurosci.,
December 1, 2001;
21(23):
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[Abstract]
[Full Text]
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L.-L. Hwang, C.-T. Chen, and N. J Dun
Mechanisms of orexin-induced depolarizations in rat dorsal motor nucleus of vagus neurones in vitro
J. Physiol.,
December 1, 2001;
537(2):
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[Abstract]
[Full Text]
[PDF]
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G. Mazzocchi, L. K. Malendowicz, F. Aragona, P. Rebuffat, L. Gottardo, and G. G. Nussdorfer
Human Pheochromocytomas Express Orexin Receptor Type 2 Gene and Display an in Vitro Secretory Response to Orexins A and B
J. Clin. Endocrinol. Metab.,
October 1, 2001;
86(10):
4818 - 4821.
[Abstract]
[Full Text]
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T. L. Horvath, S. Diano, P. Sotonyi, M. Heiman, and M. Tschop
Minireview: Ghrelin and the Regulation of Energy Balance--A Hypothalamic Perspective
Endocrinology,
October 1, 2001;
142(10):
4163 - 4169.
[Abstract]
[Full Text]
[PDF]
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T. Shirasaka, S. Miyahara, T. Kunitake, Q.-H. Jin, K. Kato, M. Takasaki, and H. Kannan
Orexin depolarizes rat hypothalamic paraventricular nucleus neurons
Am J Physiol Regulatory Integrative Comp Physiol,
October 1, 2001;
281(4):
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[Abstract]
[Full Text]
[PDF]
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W. K. Samson and M. M. Taylor
Hypocretin/orexin suppresses corticotroph responsiveness in vitro
Am J Physiol Regulatory Integrative Comp Physiol,
October 1, 2001;
281(4):
R1140 - R1145.
[Abstract]
[Full Text]
[PDF]
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Y.-F. Wang, X.-B. Gao, and A. N. van den Pol
Membrane Properties Underlying Patterns of GABA-Dependent Action Potentials in Developing Mouse Hypothalamic Neurons
J Neurophysiol,
September 1, 2001;
86(3):
1252 - 1265.
[Abstract]
[Full Text]
[PDF]
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Z.-L. Huang, W.-M. Qu, W.-D. Li, T. Mochizuki, N. Eguchi, T. Watanabe, Y. Urade, and O. Hayaishi
Arousal effect of orexin A depends on activation of the histaminergic system
PNAS,
August 1, 2001;
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[Abstract]
[Full Text]
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M. Blanco, M. Lopez, T. GarcIa-Caballero, R. Gallego, A. Vazquez-Boquete, G. Morel, R. SenarIs, F. Casanueva, C. Dieguez, and A. Beiras
Cellular Localization of Orexin Receptors in Human Pituitary
J. Clin. Endocrinol. Metab.,
July 1, 2001;
86(7):
3444 - 3447.
[Abstract]
[Full Text]
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X.-B. Gao and A. N van den Pol
Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus
J. Physiol.,
May 15, 2001;
533(1):
237 - 252.
[Abstract]
[Full Text]
[PDF]
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L. I. Kiyashchenko, B. Y. Mileykovskiy, Y.-Y. Lai, and J. M. Siegel
Increased and Decreased Muscle Tone With Orexin (Hypocretin) Microinjections in the Locus Coeruleus and Pontine Inhibitory Area
J Neurophysiol,
May 1, 2001;
85(5):
2008 - 2016.
[Abstract]
[Full Text]
[PDF]
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M. Blanco, M. López, T. GarcÍa-Caballero, R. Gallego, A. Vázquez-Boquete, G. Morel, R. SeñarÍs, F. Casanueva, C. Diéguez, and A. Beiras
Cellular Localization of Orexin Receptors in Human Pituitary
J. Clin. Endocrinol. Metab.,
April 1, 2001;
86(4):
1616 - 1619.
[Abstract]
[Full Text]
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T. S. Kilduff
Sleepy Dogs Don't Lie: A Genetic Disorder Informative About Sleep
Genome Res.,
April 1, 2001;
11(4):
509 - 511.
[Full Text]
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G. Mazzocchi, L. K. Malendowicz, L. Gottardo, F. Aragona, and G. G. Nussdorfer
Orexin A Stimulates Cortisol Secretion from Human Adrenocortical Cells through Activation of the Adenylate Cyclase-Dependent Signaling Cascade
J. Clin. Endocrinol. Metab.,
February 1, 2001;
86(2):
778 - 782.
[Abstract]
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P. Bourgin, S. Huitron-Resendiz, A. D. Spier, V. Fabre, B. Morte, J. R. Criado, J. G. Sutcliffe, S. J. Henriksen, and L. de Lecea
Hypocretin-1 Modulates Rapid Eye Movement Sleep through Activation of Locus Coeruleus Neurons
J. Neurosci.,
October 15, 2000;
20(20):
7760 - 7765.
[Abstract]
[Full Text]
[PDF]
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J.-Y. Li, S. Finniss, Y.-K. Yang, Q. Zeng, S.-Y. Qu, G. Barsh, C. Dickinson, and I. Gantz
Agouti-Related Protein-Like Immunoreactivity: Characterization of Release from Hypothalamic Tissue and Presence in Serum
Endocrinology,
June 1, 2000;
141(6):
1942 - 1950.
[Abstract]
[Full Text]
[PDF]
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C.-T. Chen, L.-L. Hwang, J.-K. Chang, and N. J. Dun
Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats
Am J Physiol Regulatory Integrative Comp Physiol,
March 1, 2000;
278(3):
R692 - R697.
[Abstract]
[Full Text]
[PDF]
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T. Shirasaka, M. Nakazato, S. Matsukura, M. Takasaki, and H. Kannan
Sympathetic and cardiovascular actions of orexins in conscious rats
Am J Physiol Regulatory Integrative Comp Physiol,
December 1, 1999;
277(6):
R1780 - R1785.
[Abstract]
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J. J. Hagan, R. A. Leslie, S. Patel, M. L. Evans, T. A. Wattam, S. Holmes, C. D. Benham, S. G. Taylor, C. Routledge, P. Hemmati, et al.
Orexin A activates locus coeruleus cell firing and increases arousal in the rat
PNAS,
September 14, 1999;
96(19):
10911 - 10916.
[Abstract]
[Full Text]
[PDF]
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P. J Emmerson and R. J Miller
Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat arcuate nucleus and ventromedial hypothalamus in vitro
J. Physiol.,
June 1, 1999;
517(2):
431 - 445.
[Abstract]
[Full Text]
[PDF]
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A. N. van den Pol
Hypothalamic Hypocretin (Orexin): Robust Innervation of the Spinal Cord
J. Neurosci.,
April 15, 1999;
19(8):
3171 - 3182.
[Abstract]
[Full Text]
[PDF]
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T. L. Horvath, S. Diano, and A. N. van den Pol
Synaptic Interaction between Hypocretin (Orexin) and Neuropeptide Y Cells in the Rodent and Primate Hypothalamus: A Novel Circuit Implicated in Metabolic and Endocrine Regulations
J. Neurosci.,
February 1, 1999;
19(3):
1072 - 1087.
[Abstract]
[Full Text]
[PDF]
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C. Peyron, D. K. Tighe, A. N. van den Pol, L. de Lecea, H. C. Heller, J. G. Sutcliffe, and T. S. Kilduff
Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems
J. Neurosci.,
December 1, 1998;
18(23):
9996 - 10015.
[Abstract]
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P.-E. Lund, R. Shariatmadari, A. Uustare, M. Detheux, M. Parmentier, J. P. Kukkonen, and K. E. O. Akerman
The Orexin OX1 Receptor Activates a Novel Ca2+ Influx Pathway Necessary for Coupling to Phospholipase C
J. Biol. Chem.,
September 29, 2000;
275(40):
30806 - 30812.
[Abstract]
[Full Text]
[PDF]
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Z.-L. Huang, W.-M. Qu, W.-D. Li, T. Mochizuki, N. Eguchi, T. Watanabe, Y. Urade, and O. Hayaishi
Arousal effect of orexin A depends on activation of the histaminergic system
PNAS,
August 14, 2001;
98(17):
9965 - 9970.
[Abstract]
[Full Text]
[PDF]
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