Heteromultimerization of cannabinoid CB1 receptor and orexin OX1 receptor generates a unique complex in which both protomers are regulated by orexin A

Ward, R. J., Pediani, J. D. and Milligan, G. (2011) Heteromultimerization of cannabinoid CB1 receptor and orexin OX1 receptor generates a unique complex in which both protomers are regulated by orexin A. Journal of Biological Chemistry, 286(43), pp. 37414-37428. (doi:10.1074/jbc.M111.287649)

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Publisher's URL: http://dx.doi.org/10.1074/jbc.M111.287649


Agonist-induced internalization was observed for both inducible and constitutively expressed forms of the cannabinoid CB<sub>1</sub> receptor. These were also internalized by the peptide orexin A, which has no direct affinity for the cannabinoid CB<sub>1</sub> receptor, but only when the orexin OX<sub>1</sub> receptor was co-expressed along with the cannabinoid CB<sub>1</sub> receptor. This effect of orexin A was concentration-dependent and blocked by OX<sub>1</sub> receptor antagonists. Moreover, the ability of orexin A to internalize the CB<sub>1</sub> receptor was also blocked by CB<sub>1</sub> receptor antagonists. Remarkably, orexin A was substantially more potent in producing internalization of the CB<sub>1</sub> receptor than in causing internalization of the bulk OX<sub>1</sub> receptor population, and this was true in cells in which the CB<sub>1</sub> receptor was maintained at a constant level, whereas levels of OX<sub>1</sub> could be varied and vice versa. Both co-immunoprecipitation and cell surface, homogenous time-resolved fluorescence resonance energy transfer based on covalent labeling of N-terminal “SNAP” and “CLIP” tags present in the extracellular N-terminal domain of the receptors confirmed the capacity of these two receptors to heteromultimerize. These studies confirm the capacity of the CB<sub>1</sub> and OX<sub>1</sub> receptors to interact directly and demonstrate that this complex has unique regulatory characteristics. The higher potency of the agonist orexin A to regulate the CB<sub>1</sub> -OX<sub>1</sub> heteromer compared with the OX<sub>1</sub> -OX<sub>1</sub> homomer present in the same cells and the effects of CB<sub>1</sub> receptor antagonists on the function of orexin A suggest an interplay between these two systems that may modulate appetite, feeding, and wakefulness.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Pediani, Dr John and Ward, Dr Richard
Authors: Ward, R. J., Pediani, J. D., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:09 September 2011
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
510631The organisational structure of class A GPCRs: implications for function and drug designGraeme MilliganMedical Research Council (MRC)G0900050Institute of Neuroscience and Psychology