GPCRomics: An Approach to Discover GPCR Drug Targets

G protein-coupled receptors (GPCRs) are targets for ∼35% of approved drugs but only ∼15% of the ∼800 human GPCRs are currently such targets. GPCRomics, the use of unbiased, hypothesis-generating methods [e.g., RNA-sequencing (RNA-seq)], with tissues and cell types to identify and quantify GPCR expression, has led to the discovery of previously unrecognized GPCRs that contribute to functional responses and pathophysiology and that may be therapeutic targets. The combination of GPCR expression data with validation studies (e.g., signaling and functional activities) provides opportunities for the discovery of disease-relevant GPCR targets and therapeutics. Here, we review insights from GPCRomic approaches, gaps in knowledge, and future directions by which GPCRomics can advance GPCR biology and the discovery of new GPCR-targeted drugs. GPCRomic analysis, currently based on mRNA studies (in particular, the use of RNAseq) is a hypothesis-generating approach that can identify and quantify previously unrecognized GPCRs. GPCRomic studies reveal that various cell types typically express >100 of the ∼360 known human endoGPCRs, including numerous orphan GPCRs. Previously unrecognized (“new”) GPCRs may be physiologically important, contribute to pathophysiology and will likely expand the utility of GPCRs as therapeutic targets in multiple disease settings. GPCRomic analyses may reveal increased GPCR mRNA expression in such disease settings and thereby new GPCRs as therapeutic targets. The therapeutic application of GPCRomic discoveries will benefit from new approaches, such as gene editing, nanobodies, aptamers and gene therapy.