Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins

Yun Zhu, Yoshihiro Miwa, Akihiro Yamanaka, Toshihiko Yada, Megumi Shibahara, Yoichiro Abe, Takeshi Sakurai, Katsutoshi Goto

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Abstract

Signal transduction pathways of orexin receptors were examined using a nerve-like cell line transfected with orexin receptor type-1 (OX1R) and orexin receptor type-2 (OX2R). Forskolin-stimulated cyclic adenosine 3,5-monophosphate (cAMP) accumulation in OX2R-expressing cells was inhibited by orexin in a dose-dependent manner, and the effect was abolished by pretreatment with pertussis toxin (PTX). The inhibitory effect of orexin on forskolin-stimulated cAMP accumulation was not observed in OXIR-expressing cells. Administration of orexin to these cells resulted in a transient increase of intracellular calcium concentration ([Ca2+]i). Orexin-stimulated increases in [Ca2+]i in OX1R- or OX2R-expressing cells were not affected by the PTX pretreatment. These observations suggest that OX1R couples exclusively to PTX-insensitive G-proteins, while OX2R couples to both PTX-sensitive and -insensitive G-proteins. To examine the relative contributions of these G-proteins in OX2R-mediated activation of neurons, we used histaminergic tuberomammillary nucleus neurons, in which OX2R is abundantly expressed. We found that a phospholipase C (PLC)-inhibitor, U73122, inhibits orexin-mediated neuronal activation, but PTX showed no effect on it. This suggests that although OX2R couples to multiple G-proteins, activation of neurons by orexins through OX2R is mediated via a PTX-insensitive, PLC dependent pathway.

Original languageEnglish
Pages (from-to)259-266
Number of pages8
JournalJournal of Pharmacological Sciences
Volume92
Issue number3
DOIs
Publication statusPublished - 2003 Jul 1
Externally publishedYes

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Keywords

  • Calcium mobilization
  • G-protein
  • Orexin
  • Orexin receptor
  • cAMP

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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