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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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