Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A.
Summary of "Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A."
Agonist-induced internalization was observed for both inducible and constitutively expressed forms of the cannabinoid CB(1) receptor. These were also internalized by the peptide orexin A, which has no direct affinity for the cannabinoid CB(1) receptor, but only when the orexin OX(1) receptor was co-expressed along with the cannabinoid CB(1) receptor. This effect of orexin A was concentration-dependent and blocked by OX(1) receptor antagonists. Moreover, the ability of orexin A to internalize the CB(1) receptor was also blocked by CB(1) receptor antagonists. Remarkably, orexin A was substantially more potent in producing internalization of the CB(1) receptor than in causing internalization of the bulk OX(1) receptor population, and this was true in cells in which the CB(1) receptor was maintained at a constant level, whereas levels of OX(1) 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(1) and OX(1) 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(1)-OX(1) heteromer compared with the OX(1)-OX(1) homomer present in the same cells and the effects of CB(1) receptor antagonists on the function of orexin A suggest an interplay between these two systems that may modulate appetite, feeding, and wakefulness.
Affiliation
From the Molecular Pharmacology Group, Institute of Neuroscience and Psychology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
Journal Details
This article was published in the following journal.
Name: The Journal of biological chemistry
ISSN: 1083-351X
Pages: 37414-28
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21908614
- DOI: http://dx.doi.org/10.1074/jbc.M111.287649
Medical and Biotech [MESH] Definitions
Receptor, Cannabinoid, Cb2
A subclass of cannabinoid receptor found primarily on immune cells where it may play a role modulating release of CYTOKINES.
Receptor, Cannabinoid, Cb1
A subclass of cannabinoid receptor found primarily on central and peripheral NEURONS where it may play a role modulating NEUROTRANSMITTER release.
Receptor, Erbb-2
A cell surface protein-tyrosine kinase receptor that is found to be overexpressed in a significant number of adenocarcinomas. It has extensive homology to and can heterodimerize with the EGF receptor (RECEPTOR, EPIDERMAL GROWTH FACTOR), the erbB-3 receptor (RECEPTOR, ERBB-3) and the erbB-4 receptor. Activation of the erbB-2 receptor occurs during heterodimer formation with a ligand-bound erbB receptor family members.
Receptor, Erbb-3
A cell surface protein-tyrosine kinase receptor that is specific for NEUREGULINS. It has extensive homology to and can heterodimerize with the EGF Receptor (RECEPTOR, EPIDERMAL GROWTH FACTOR) and the erbB-2 receptor (RECEPTOR, ERBB-2). Overexpression of the erbB-3 receptor is associated with tumorigenesis.
T-cell Antigen Receptor Specificity
The property of the T-CELL RECEPTOR which enables it to react with some antigens and not others. The specificity is derived from the structure of the receptor's variable region which has the ability to recognize certain antigens in conjunction with the MAJOR HISTOCOMPATIBILITY COMPLEX molecule.
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