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This Article Full Text Full Text (PDF) All Versions of this Article: 92/6/3183    most recent 01222.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Hoang, Q. V. Articles by Nakajima, Y. Search for Related Content PubMed PubMed Citation Articles by Hoang, Q. V. Articles by Nakajima, Y.

Orexin (Hypocretin) Effects on Constitutively Active Inward Rectifier K⁺ Channels in Cultured Nucleus Basalis Neurons

¹Department of Anatomy and Cell Biology and ²Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois 60612-7308

Submitted 16 December 2003; accepted in final form 16 July 2004

Orexins are excitatory transmitters implicated in sleep disorders. Because orexins were discovered only recently, their ionic and signal transduction mechanisms have not been well clarified. We recently reported that orexin A (OXA) inhibits G protein–coupled inward rectifier K⁺ (GIRK) channels in cultured locus coeruleus and nucleus tuberomammillaris neurons. Other work in our laboratory revealed the existence of a novel inward rectifier K⁺ channel (KirNB), which is located in cholinergic neurons of the nucleus basalis (NB) and possesses unique single-channel characteristics. The mean open time is considerably shorter in KirNB than in Kir2.0 channels. Constitutive activity and a smaller unitary conductance set KirNB apart from cloned Kir3.0 channels. Previously, we found that substance P excites NB neurons by inhibiting KirNB channels. Here we show that orexins suppress KirNB channel activity, likely leading to neuronal excitation. Electrophysiological studies were performed on cultured NB neurons from the basal forebrain. OXA application decreased whole cell conductance through a pertussis toxin (PTX)-insensitive G protein. The OXA-suppressed current was inwardly rectifying with a reversal potential around E_K. Single-channel recordings of NB neurons revealed that constitutively active KirNB channels were transiently inhibited by OXA. Okadaic acid pretreatment abolished the recovery. The results suggest that OXA inhibition of KirNB is mediated by a PTX-insensitive G protein (i.e., G_q/11), which eventually results in channel phosphorylation. Recovery from this inhibition is by dephosphorylation. These results, taken together with our previous study, suggest that orexin receptors can elicit neuronal excitation through at least two families of inward rectifier K⁺ channels: GIRK and KirNB channels.

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