Abstract
The neuropeptides orexins/hypocretins are essential for normal wakefulness and energy balance, and disruption of their function causes narcolepsy and obesity. Although much is known of the role of orexins in sleep/wake behavior, it remains unclear how they stimulate feeding and metabolism. One of the main targets of orexinergic neurons is the arcuate nucleus (ARC) of the hypothalamus, which plays a key role in feeding and energy homeostasis. By combining patch-clamp and RT-multiplex PCR analysis of individual neurons in mouse brain slices, we show that an electrophysiologically distinct subset of ARC neurons coexpress orexin receptors and glutamate decarboxylase-67 and are excited by orexin. Acting on postsynaptic orexin type 2 receptors, orexin activates a sodium-calcium exchange current, thereby depolarizing the cell and increasing its firing frequency. Because GABA is a potent stimulus for feeding, in both the ARC and its main projection site, these results suggest a mechanism for how orexin may control appetite.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arcuate Nucleus of Hypothalamus / cytology
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Arcuate Nucleus of Hypothalamus / drug effects*
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Arcuate Nucleus of Hypothalamus / metabolism
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Calcium / metabolism
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Carrier Proteins / pharmacology*
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Chelating Agents / pharmacology
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Egtazic Acid / analogs & derivatives*
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Egtazic Acid / pharmacology
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Electrophysiology
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Energy Metabolism / physiology
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Glutamate Decarboxylase / biosynthesis
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins*
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Isoenzymes / biosynthesis
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Male
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Mice
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Mice, Inbred C57BL
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Neurons / chemistry
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Neurons / drug effects
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Neurons / metabolism*
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Neuropeptides / pharmacology*
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Orexin Receptors
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Orexins
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Patch-Clamp Techniques
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Polymerase Chain Reaction
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide / biosynthesis
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Sodium-Calcium Exchanger / drug effects
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Sodium-Calcium Exchanger / metabolism*
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gamma-Aminobutyric Acid / metabolism*
Substances
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Carrier Proteins
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Chelating Agents
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Neuropeptides
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Orexin Receptors
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Orexins
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Sodium-Calcium Exchanger
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Egtazic Acid
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gamma-Aminobutyric Acid
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Glutamate Decarboxylase
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glutamate decarboxylase 1
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1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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Calcium