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Heterodimerization of mouse orexin type 2 receptor variants and the effects on signal transduction
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Wang, Chunmei, Pan, Yanyou, Zhang, Rumin, Bai, Bo, Chen, Jing and Randeva, Harpal S. (2014) Heterodimerization of mouse orexin type 2 receptor variants and the effects on signal transduction. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1843 (Number 3). pp. 652-663. doi:10.1016/j.bbamcr.2013.12.010 ISSN 0167-4889.
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Official URL: http://dx.doi.org/10.1016/j.bbamcr.2013.12.010
Abstract
Orexin-A and Orexin-B play important roles in many physiological processes in which Orexins orchestrate diverse downstream effects via two G-protein coupled receptors: Orexin1R and Orexin2R. Two alternative C-terminus splice variants of the mouse Orexin receptors mOX2αR and mOX2βR have recently been identified. This study explored the possibility of heterodimerization between mOX2αR and mOX2βR, and investigated novel signal transduction characteristics after stimulation. The dimerization of mOX2αR and mOX2βR was confirmed by BRET and co-immunoprecipitation assays. Meanwhile, in HEK293 cells, co-expression of mOX2αR and mOX2βR resulted in a strengthened increase in activation of ERK1/2, with maximal activation at 5 min and 100 nM. Furthermore, heterodimerization also elicits stronger intracellular Ca2 + elevation after Orexin(s) stimulation, followed by a slower decline in intracellular Ca2 + to a steady endpoint. Protein Kinase C Inhibitor significantly inhibited these downstream effects. In addition, the cAMP response element reporter activities were significantly reduced, whereas the serum response element luciferase and the T-lymphocyte activation of nuclear factor-responsive element reporter activity were significantly up-regulated after Orexin(s) stimulation. Besides, Orexin-A/-B induced a significantly higher rate of HEK293 cell proliferation in cells co-expressing mOX2αR/mOX2βR compared to the control group. Taken together, we provide conclusive evidence that mOX2αR can form a functional heterodimer with mOX2βR and this leads to increased PKC and decreased protein kinase A activity by ERK signal pathway leading to a significant increase in cell proliferation. The nature of this signaling pathway has significant implications for the role of Orexin in the regulation of physiological processes including the homeostasis of feeding.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | ||||
| Publisher: | Elsevier | ||||
| ISSN: | 0167-4889 | ||||
| Official Date: | 2014 | ||||
| Dates: |
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| Volume: | Volume 1843 | ||||
| Number: | Number 3 | ||||
| Page Range: | pp. 652-663 | ||||
| DOI: | 10.1016/j.bbamcr.2013.12.010 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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