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

2005; National Academy of Sciences; Volume: 102; Issue: 25 Linguagem: Inglês

10.1073/pnas.0501112102

1091-6490

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

Biochemical Analysis and Sensing Techniques

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.