G protein coupled receptor heterodimerization leads to distinct signaling

Protein‐protein interactions govern a large number of biological processes. It is well established that a variety of cell surface receptors interact with each other to form dimers and that this is essential for their function. A number of G‐protein coupled receptors have been recently shown to physically associate and in some cases this association has been found to alter their function such as ligand binding, signaling and trafficking properties. We have used opioid receptors as a model system with the intent of examining the consequences of receptor‐receptor interactions on analgesia and addiction. Two types of opioid receptors, μ and δ physically associate with each other to form heterodimers and this leads to changes in agonist affinity, efficacy and/or potency. Using heterodimer‐selective antibodies, we show that opiate treatment, under conditions that lead to the development of tolerance, induces upregulation of the μ‐δ heterodimer in distinct brain regions. We also show that the upregulated heterodimer constitutively recruits β‐arrestin and this leads to changes in the spatio‐temporal dynamics of signaling. This, in turn, leads to differential activation of transcription factors resulting in long lasting changes in gene expression. These results, for the first time, show that the G protein‐coupled receptor heterodimer can function as a novel signaling unit. Taken with the fact the levels of the heterodimer levels tend to be upregulated during pathology, these results suggest that the heterodimer represents a unique target for the development of novel therapeutics for the treatment of pathologies involving G protein‐coupled receptors.