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.opioid

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…The concept of GPCR oligomerization was later confirmed in 1998-1999 by studies reporting that two nonfunctional class C GPCR monomers, GABA B1 and GABA B2 , assembled in a signaling heterodimer (Marshall et al, 1999a). In the years that followed, several groups provided direct evidence for the existence of receptor complexes formed by GPCR (Fuxe et al, 1998;Bockaert and Pin, 1999;Marshall et al, 1999b;Xie et al, 1999;Franco et al, 2000;Lee et al, 2000;Overton and Blumer, 2000;Zeng and Wess, 2000;Angers et al, 2001;Dean et al, 2001;Kenakin, 2002;Waldhoer et al, 2005).…”

Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

“…We have recently reported on ligands that selectively target ␦-heterodimers that are localized in the spinal cord (29,37). Here, we describe an extension of this approach for the design of bivalent ligands that target -␦ heterodimeric opioid receptors in the brain.…”

Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations

“…Like many other GPCRs opioid receptors undergo dimerization and may be engaged in cross-signaling as shown recently for the heterodimer of the  2A adrenergic receptor and µOR [18]. It was also proposed by Waldhoer et al [19] that 6'-GNTI selectively activates opioid receptor heterodimers, OR-OR, but not homodimers. 6'-GNTI is an agonist of OR but an antagonist of OR so there is a possibility of cross-talk between these receptors.…”