The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO

G protein-coupled receptors (GPCRs) are critical for cardiovascular physiology. Cardiac cells express >100 nonchemosensory GPCRs, indicating that important physiological and potential therapeutic targets remain to be discovered. Moreover, there is a growing appreciation that members of the large, distinct taste and odorant GPCR families have specific functions in tissues beyond the oronasal cavity, including in the brain, gastrointestinal tract and respiratory system. To date, these chemosensory GPCRs have not been systematically studied in the heart. We performed RT-qPCR taste receptor screens in rodent and human heart tissues that revealed discrete subsets of type 2 taste receptors (TAS2/Tas2) as well as Tas1r1 and Tas1r3 (comprising the umami receptor) are expressed. These taste GPCRs are present in cultured cardiac myocytes and fibroblasts, and by in situ hybridization can be visualized across the myocardium in isolated cardiac cells. Tas1r1 gene-targeted mice (Tas1r1^Cre/Rosa26^tdRFP) strikingly recapitulated these data. In vivo taste receptor expression levels were developmentally regulated in the postnatal period. Intriguingly, several Tas2rs were upregulated in cultured rat myocytes and in mouse heart in vivo following starvation. The discovery of taste GPCRs in the heart opens an exciting new field of cardiac research. We predict that these taste receptors may function as nutrient sensors in the heart.

G‐protein‐coupled receptors (GPCRs) are key mediators in cardiovascular physiology, yet frontline therapies for heart disease target only a small fraction of the cardiac GPCR repertoire. Moreover, there is emerging evidence that GPCRs implicated in taste (Tas1r and Tas2rs) have specific functions beyond the oral cavity. Our recent description of these receptors in heart tissue foreshadows a potential novel role in cardiac cells. In this study, we identified novel agonist ligands for cardiac‐Tas2rs to enable the functional investigation of these receptors in heart tissue. Five Tas2rs cloned from heart tissue were screened against a panel of 102 natural or synthetic bitter compounds in a heterologous expression system. We identified agonists for Tas2r108, Tas2r137, and Tas2r143 that were then tested in Langendorff‐perfused mouse hearts (from 8‐wk‐old male C57BL/6 mice). All Tas2r agonists tested exhibited concentration‐dependent effects, with agonists for Tas2r108 and Tas2r137, leading to a ~40% decrease in left ventricular developed pressure and an increase in aortic pressure, respectively. These responses were abrogated in the presence of Gα ₁ and Gβγ inhibitors (pertussis toxin and gallein). This study represents the first demonstration of profound Tas2r agonist‐induced, G protein‐dependent effects on mouse heart function.—Foster, S. R., Blank, K., See Hoe, L. E., Behrens, M., Meyerhof, W., Peart, J. N., Thomas, W. G., Bitter taste receptor agonists elicit G‐protein‐dependent negative inotropy in the murine heart. FASEB J. 28, 4497–4508 (2014). www.fasebj.org

In response to infection or injury, the body mounts an inflammatory immune response in order to neutralize pathogens and promote tissue repair. The key effector cells for these responses are the leukocytes (white blood cells), which are specifically recruited to the site of injury. However, dysregulation of the inflammatory response, characterized by the excessive migration of leukocytes to the affected tissues, can also lead to chronic inflammatory diseases. Leukocyte recruitment is regulated by inflammatory mediators, including an important family of small secreted chemokines and their corresponding G protein‐coupled receptors expressed in leukocytes. Unsurprisingly, due to their central role in the leukocyte inflammatory response, chemokines and their receptors have been intensely investigated and represent attractive drug targets. Nonetheless, the full therapeutic potential of chemokine receptors has not been realized, largely due to the complexities in the chemokine system. The determination of chemokine–receptor structures in recent years has dramatically shaped our understanding of the molecular mechanisms that underpin chemokine signaling. In this review, we summarize the contemporary structural view of chemokine–receptor recognition, and describe the various binding modes of peptide and small‐molecule ligands to chemokine receptors. We also provide some perspectives on the implications of these data for future research and therapeutic development.Importance Statement: Given their central role in the leukocyte inflammatory response, chemokines and their receptors are considered as important regulators of physiology and viable therapeutic targets. In this review, we provide a summary of the current understanding of chemokine: chemokine–receptor interactions that have been gained from structural studies, as well as their implications for future drug discovery efforts.