Understanding the impact of variation in the GPCR signaling system
G-protein-coupled receptors (GPCRs) participate in diverse physiological processes, ranging from sensory responses such as vision, taste and smell to those regulating behavior, the immune and the cardiac system among others. The ~800 human GPCRs sense diverse signaling molecules such as hormones and neurotransmitters to allosterically activate the associated G proteins, which in turn regulate intracellular signaling. In this manner, GPCRs regulate virtually every aspect of human physiology. Not surprisingly, GPCRs are the targets of over one-third of all prescribed human drugs.
In this presentation, I will first discuss how one could leverage data on sequence changes across diverse species to infer selectivity determinants of GPCR-G-protein binding, which is critical to elicit the right intracellular response. I will then discuss how one could exploit data on completely sequenced genomes of over 60,000 individuals from the human population to gain insights into natural receptor variation, which can result in variable drug response. Finally, I will present ongoing work wherein by studying transcriptome data from over 30 different tissues in humans, one could begin to understand how alternative splicing can create diversity in GPCR signaling components, which may contribute to tissue-specific differences in receptor signaling.