| Abstract No.: | C-B3025 |
| Country: | Canada |
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| Title: | ROLE OF ATP-SENSITIVE POTASSIUM CHANNELS IN OREXIN NEURONS |
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| Authors/Affiliations: | 1 Matthew Parsons*; 1 Christian Alberto; 1 Michiru Hirasawa;
1 Memorial University, St. John's, NL, Canada
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| Content: | Orexin neurons in the hypothalamus are known to be activated by low extracellular levels of glucose. Increased orexin activity promotes arousal, locomotor activity and motivation required to stimulate energy intake, suggesting that the glucose-sensing ability of orexin neurons plays a critical role in glucose homeostasis. However, in situations of prolonged hypoglycemia or food scarcity, such excitation may be detrimental to the health of orexin neurons as well as their efferent targets as the orexins are excitatory neuropeptides. OBJECTIVES: ATP sensitive potassium (KATP) channels play a well-established role in linking metabolism to cellular excitability. It was of interest to determine the expression of KATP channel subunits in orexin neurons and whether or not these channels play a role in the inhibition of orexin neurons under experimental conditions of intense metabolic inhibition. METHODS: Dual-label immunofluorescence and confocal microscopy were used to determine the expression of KATP channel subunits (Kir6.1 and Kir6.2) within the orexin-containing area of the hypothalamus. Conventional whole cell and perforated patch recordings were obtained from orexin neurons in acute hypothalamic slices of male Sprague-Dawley rats to determine the effects of metabolic inhibition and known KATP channel openers on these neurons. Orexin neurons were identified based on their electrophysiological characteristics and post-hoc immunohistochemistry. RESULTS: Orexin neurons displayed large outward currents in response to both metabolic inhibition by the mitochondrial uncoupler CCCP and dialysis with an ATP-free internal solution. Both of these effects were prevented or reversed by the KATP channel blocker glibenclamide. Glibenclamide had no effect on its own suggesting that these channels are closed under normal conditions and hyperpolarize orexin neurons when activated by metabolic stress. A glibenclamide-sensitive outward current was also observed following bath application of the SUR1-containing KATP opener diazoxide whereas little response was seen following application of the SUR2-containing opener pinacidil. In agreement with the electrophysiological data, multi-label immunofluorescence revealed co-localization of KATP channel subunits Kir6.1 and Kir6.2 on orexin neurons. CONCLUSION: The present data suggests a novel mechanism of KATP-dependent suppression of orexin neuron activity which may play a role in neuroprotection during periods of severe or prolonged low-energy states. |
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