A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers

Maria Waldhoer, Jamie Fong, Robert M. Jones, Mary M. Lunzer, Shiv K. Sharma, Evi Kostenis, Philip S. Portoghese, Jennifer L. Whistler

Research output: Contribution to journalArticle

268 Citations (Scopus)

Abstract

There has been much speculation regarding the functional relevance of G protein-coupled receptor heterodimers, primarily because demonstrating their existence in vivo has proven to be a considerable challenge. Here we show that the opioid agonist ligand 6′-guanidinonaltrindole (6′-GNTI) has the unique property of selectively activating only opioid receptor heterodimers but not homomers. Importantly, 6′-GNTI is an analgesic, thereby demonstrating that opioid receptor heterodimers are indeed functionally relevant in vivo. However, 6′-GNTI induces analgesia only when it is administered in the spinal cord but not in the brain, suggesting that the organization of heterodimers is tissue-specific. This study demonstrates a proof of concept for tissue-selective drug targeting based on G protein-coupled receptor heterodimerization. Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects.

Original languageEnglish (US)
Pages (from-to)9050-9055
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number25
DOIs
StatePublished - Jun 21 2005

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G-Protein-Coupled Receptors
Opioid Receptors
Opioid Analgesics
Analgesics
Drug Delivery Systems
Analgesia
Spinal Cord
Ligands
Brain
6'-guanidinonaltrindole

Keywords

  • Opioid

Cite this

A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. / Waldhoer, Maria; Fong, Jamie; Jones, Robert M.; Lunzer, Mary M.; Sharma, Shiv K.; Kostenis, Evi; Portoghese, Philip S.; Whistler, Jennifer L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 25, 21.06.2005, p. 9050-9055.

Research output: Contribution to journalArticle

Waldhoer, Maria ; Fong, Jamie ; Jones, Robert M. ; Lunzer, Mary M. ; Sharma, Shiv K. ; Kostenis, Evi ; Portoghese, Philip S. ; Whistler, Jennifer L. / A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 25. pp. 9050-9055.
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