GPCR Dimers Are For Real

Science's STKE  28 Jun 2005:
Vol. 2005, Issue 290, pp. tw234
DOI: 10.1126/stke.2902005tw234

Waldhoer et al. report new evidence to support the notion that heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors can signal as heterodimers in vivo. The authors noted that the opioid receptor agonist 6′-guanidinonaltrindole (6′-GNTI) was a more potent inhibitor of signaling in cells expressing both kappa opioid peptide (KOP-Rs) and delta opioid peptide receptors (DOP-Rs). Selective agonists for either the KOP-Rs or DOP-Rs could block 6′-GNTI-mediated signaling in cells expressing both receptors, which indicates that 6′-GNTI was acting on heterodimers. Binding affinities for the specific antagonists were different from those measured in cells expressing only one receptor type, which may indicate that it will be possible to selectively modulate heterodimer function with therapeutic agents. Indeed, in mice, 6′-GNTI was a more potent and effective analgesic when applied to the spinal cord than when applied to the brain. Such a tissue-selective agonist could be very useful, because side effects of opiates like morphine are reduced when the drug is applied directly to the spinal cord.

M. Waldhoer, J. Fong, R. M. Jones, M. M. Lunzer, S. K. Sharma, E. Kostenis, P. S. Portoghese, J. L. Whistler, A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc. Natl. Acad. Sci. U.S.A. 102, 9050-9055 (2005). [Abstract] [Full Text]