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 (Tas1r1Cre/Rosa26tdRFP) 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.

The peptide hormone calcitonin is widely used therapeutically in the treatment of bone disorders such as Paget's disease, osteoporosis, and the hypercalcemia of some malignancies. However, emerging evidence suggests the actions of calcitonin via its G protein-coupled receptor, the calcitonin receptor, may not be limited to bone. Calcitonin receptors have also been identified in the central nervous system, testes, skeletal muscle, lymphocytes, and the placenta. We are now becoming aware that the complexity of the calcitonin response mediated by the calcitonin receptor can be influenced by accessory proteins, receptor isoforms, genetic polymorphisms, developmental and/or transcriptional regulation, feedback inhibition, and the specific cellular or tissue background. This article discusses what is known about the molecular and pharmacological actions of the calcitonin receptor and highlights areas of current research.

SummaryThe angiotensin type 1 receptor (AT 1 R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT 1 R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT 1 R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT 1 R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT 1 R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.

Calcitonins are 32-amino acid peptide hormones with both peripheral and central actions mediated via specific cell surface receptors, which belong to the class II subfamily of G protein-coupled receptors. Understanding receptor function, particularly in terms of ligand recognition by calcitonin receptors, may aid in the rational design of calcitonin analogs with increased potency and improved selectivity. To directly identify sites of proximity between calcitonin and its receptor, we carried out photoaffinity labeling studies followed by protein digestion and mapping of the radiolabeled photoconjugated receptor. . These results provide the first direct demonstration of a contact domain between salmon calcitonin and its receptor and will contribute toward modeling of the calcitonin-receptor interface. Calcitonins (CTs)1 are 32-amino acid peptide hormones, secreted from the thyroid gland, whose most recognized action is the inhibition of osteoclast-mediated bone resorption (1). Calcitonin receptors (CTRs), however, are expressed widely in both peripheral and central tissues, and CTs exert a wide range of actions including modulation of ion excretion in the kidney, inhibition of appetite, and gastric acid secretion via both peripheral and central mechanisms as well as affecting embryological implantation and development and sperm function (1-3). CTs, through their action on osteoclasts and to a lesser extent in the kidney, are widely used clinically in the treatment of bone-related disorders such as hypercalcemia of malignancy and osteoporosis but are most effective in conditions that have high bone turnover such as Paget's disease (1, 2).CT peptides, derived from different species, fall into three broad classes according to structural and biological similarities: teleost/avian, exemplified by salmon CT (sCT); artiodactyl; and rodent/human. Of these, the teleost/avian class has the highest affinity and efficacy, although the relative potency of CTs varies according to the species of receptor under study (1, 4). As a consequence of its higher potency and in vivo stability, sCT is the most common form of CT used therapeutically.The CTR is a member of the class II subfamily of G proteincoupled receptors, which includes the receptors for peptide hormones such as parathyroid hormone (PTH) and PTH-related protein, secretin, vasoactive intestinal polypeptide, and glucagons (5). These receptors exhibit homology with each other and have a number of common structural features including a large amino-terminal domain that contains at least one site of N-linked glycosylation and 6 conserved cysteines that yield a common pattern of disulfide bonding (6, 7). The human CTR has two common splice variants that differ by the absence or presence of a 16-amino acid insert in intracellular domain 1; these receptors have been designated hCTRa and hCTRb by the IUPHAR receptor nomenclature subcommittee (8). Of these two variants, hCTRa is the most prevalent isoform (8 -10).Little is known about the molecular nature of the interaction betwe...