G-protein-coupled receptor heterodimerization modulates receptor function

Bryen A. Jordan, Lakshmi A. Devi

Research output: Contribution to journalArticle

905 Citations (Scopus)

Abstract

The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and μ, that mediate these diverse effects. 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 homodimers. Moreover, two non functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. 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.

Original languageEnglish (US)
Pages (from-to)697-700
Number of pages4
JournalNature
Volume399
Issue number6737
DOIs
StatePublished - Jun 17 1999
Externally publishedYes

Fingerprint

Opioid Receptors
G-Protein-Coupled Receptors
Pharmacology
Physiological Phenomena
Dimerization
Molecular Cloning
Analgesia
Opioid Analgesics
Signal Transduction
Ligands

ASJC Scopus subject areas

  • General

Cite this

G-protein-coupled receptor heterodimerization modulates receptor function. / Jordan, Bryen A.; Devi, Lakshmi A.

In: Nature, Vol. 399, No. 6737, 17.06.1999, p. 697-700.

Research output: Contribution to journalArticle

Jordan, Bryen A. ; Devi, Lakshmi A. / G-protein-coupled receptor heterodimerization modulates receptor function. In: Nature. 1999 ; Vol. 399, No. 6737. pp. 697-700.
@article{4c7ef6f26405426c8d0d47651f3472af,
title = "G-protein-coupled receptor heterodimerization modulates receptor function",
abstract = "The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and μ, that mediate these diverse effects. 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 homodimers. Moreover, two non functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. 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.",
author = "Jordan, {Bryen A.} and Devi, {Lakshmi A.}",
year = "1999",
month = "6",
day = "17",
doi = "10.1038/21441",
language = "English (US)",
volume = "399",
pages = "697--700",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6737",

}

TY - JOUR

T1 - G-protein-coupled receptor heterodimerization modulates receptor function

AU - Jordan, Bryen A.

AU - Devi, Lakshmi A.

PY - 1999/6/17

Y1 - 1999/6/17

N2 - The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and μ, that mediate these diverse effects. 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 homodimers. Moreover, two non functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. 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.

AB - The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, δ, κ and μ, that mediate these diverse effects. 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 homodimers. Moreover, two non functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. 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.

UR - http://www.scopus.com/inward/record.url?scp=0033578005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033578005&partnerID=8YFLogxK

U2 - 10.1038/21441

DO - 10.1038/21441

M3 - Article

VL - 399

SP - 697

EP - 700

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6737

ER -