G-protein-coupled receptor heterodimerization modulates receptor function (original) (raw)

Nature volume 399, pages 697–700 (1999)Cite this article

Abstract

The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function1. Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and µ, that mediate these diverse effects2,3. Little is known about the ability of the receptors to interact to form new functional structures, the simplest of which would be a dimer. Structural and biochemical studies show that other G-protein-coupled receptors (GPCRs) interact to form homodimers4,5. Moreover, two non-functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function6,7,8,9,10,11. However, heterodimerization between two fully functional receptors has not been documented. Here we provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, κ and δ. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the κ–δ heterodimer synergistically binds highly selective agonists and potentiates signal transduction. Thus, heterodimerization of these GPCRs represents a novel mechanism that modulates their function.

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Acknowledgements

We thank L. Fricker and S. Cvejic for critical reading of the manuscript and P.Schiller for the gift of TIPPΨ. This work is supported in part by grants from the NIH (NIDA and NINDS).

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  1. Department of Pharmacology, New York University School of Medicine, New York, 10016, New York, USA
    Bryen A. Jordan & Lakshmi A. Devi

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  1. Bryen A. Jordan
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  2. Lakshmi A. Devi
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Correspondence toLakshmi A. Devi.

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Jordan, B., Devi, L. G-protein-coupled receptor heterodimerization modulates receptor function .Nature 399, 697–700 (1999). https://doi.org/10.1038/21441

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