Expression of different adenylyl cyclase isoforms impacts ligand bias downstream of the kappa opioid receptor

Abstract

Functionally selective (or biased) ligands have been widely pursued in recent years as a way to target G protein‐coupled receptors (GPCRs) in a more selective manner. The promise of biased signaling is that by specifically activating only a subset of a receptor's responses, therapeutic effects can be achieved and adverse effects prevented. Molecular studies of biased ligands are commonly carried out in cell lines, and many of them use cyclic AMP accumulation as a readout of G protein activation. The production of cyclic AMP is catalyzed by adenylyl cyclases (ACs). In humans there are 10 different isoforms of ACs, which diverge in their expression patterns and regulatory properties. In the present study, we examined if the expression of different AC isoforms in a cell line could result in different bias profiles for ligands of the kappa opioid receptor (KOR). We employed one biased and two reference ligands and showed that there were significant changes in potency as well as in bias factors depending on the AC isoform that was expressed in our cellular system. Our results support the idea that selection of an appropriate cellular model is an invaluable step in studies of functional selectivity. Moreover, using cells that match the AC expression pattern of the tissue where the compound is predicted to act can lead to more relevant results when cyclic AMP is used as a readout of G protein activation.Support or Funding InformationThis work was supported by National Institute on Drug Abuse grant R01DA031927.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.