Oligomerization of opioid receptors with β2-adrenergic receptors: A role in trafficking and mitogen-activated protein kinase activation

B. A. Jordan, N. Trapaidze, I. Gomes, R. Nivarthi, L. A. Devi

Research output: Contribution to journalArticle

285 Scopus citations

Abstract

G-protein-coupled receptors (GPCRs) have recently joined the list of cell surface receptors that dimerize. Dimerization has been shown to alter the ligand-binding, signaling, and trafficking properties of these receptors. Recent studies have shown that GPCRs heterodimerize with closely related members, resulting in the modulation of their function. In this study, we have attempted to determine whether members of GPCR superfamilies that couple to different families of G-proteins can associate and form oligomers. We chose the β2 adrenergic receptor that couples to stimulatory G-proteins and δ & κ opioid receptors that couple to inhibitory G-proteins. β2 and δ receptors undergo robust agonist-mediated endocytosis, whereas κ receptors do not. We find that when coexpressed, β2 receptors can form heteromeric complexes with both δ and κ receptors. This heterooligomerization does not significantly alter the ligand binding or coupling properties of the receptors. However, it affects the trafficking properties of the receptors. For example, we find that δ receptors, when coexpressed with β2 receptors, undergo isoproterenol-mediated endocytosis. Conversely, β2 receptors in these cells undergo etorphine-mediated endocytosis. However, β2 receptors, when coexpressed with κ receptors, undergo neither opioid- nor isoproterenol-mediated endocytosis. Moreover, these cells exhibit a substantial decrease in the isoproterenol-induced phosphorylation of mitogen-activated protein kinases. Taken together, these results provide direct evidence of heteromerization of GPCRs that couple to different types of G-proteins, which results in the modulation of receptor trafficking and signal transduction.

Original languageEnglish (US)
Pages (from-to)343-348
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number1
DOIs
StatePublished - Jan 2 2001
Externally publishedYes

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Keywords

  • Dimers
  • Endocytosis
  • G-protein-coupled receptor
  • Heterodimerization
  • Receptor subtypes

ASJC Scopus subject areas

  • General

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