title: A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers.
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.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Waldhoer
authors.forename: Jamie
authors.initials: J
authors.lastname: Fong
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D002460:Cell Line; D019281:Dimerization; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D007700:Kinetics; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: C503316:6'-guanidinonaltrindole; D000700:Analgesics; D006146:Guanidines; D043562:Receptors, G-Protein-Coupled; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-