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* To whom correspondence should be addressed. E-mail: yasukon{at}uic.edu.
Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress GIRK channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and the nucleus tuberomammillaris (TM) were used, as well as HEK293A cells transfected with GIRK1 and 2, either human orexin receptor type 1 (OX1R) or type 2 (OX2R), mu opioid receptor and GFP cDNAs. In GTP
S-loaded cells, orexin A (OXA, 3 µM) inhibited GIRK currents that had previously been activated by somatostatin (in LC cells), nociceptin (TM cells) or the mu opioid agonist DAMGO (HEK cells). In GTP-loaded HEK cells, in which GIRK currents were not pre-activated, OXA induced a biphasic response through both types of orexin receptors: an initial current increase and a subsequent decrease to below resting levels. I-V relationships revealed that both the OXA-induced and suppressed currents are inwardly rectifying with reversal potentials around EK. The OXA-induced initial current was partially pertussis toxin (PTX)-sensitive and partially PTX-insensitive, whereas the OXA-suppressed current was PTX-insensitive. These data suggest that orexin receptors couple with more than one type of G protein, including PTX-sensitive (such as Gi/o) and PTX-insensitive (such as Gq/11) G proteins. The modulation of GIRK channels by orexins may be one of the cellular mechanisms for the regulation of brain nuclei (e.g., LC and TM) that are crucial for arousal, sleep, and appetite.
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