Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

Abstract

Cardiac function is regulated by many hormones and neurotransmitters that exert their physiological effects through the activation of G protein-coupled receptors (GPCRs). Identification of new GPCRs that might display a specific pattern of expression within the heart and differentially regulate specific cardiac functions represents an important issue for the development of new drugs. Indeed, highly targeted receptors represent only a small percentage of known GPCRs. Here, we quantified the expression of 395 endoGPCRs (all GPCRs excluding taste and odorant receptors) in male mouse right and left atria and ventricles by using high-throughput real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and focused on the 135 most highly expressed transcripts. No cardiac functional data are available for almost half of these receptors; therefore, linking GPCR expression patterns to cardiac function has allowed us to provide new insights into the possible function of some of these receptors. Indeed, ventricles and atria are both contractile; however, the latter, and especially the right atrium, are central to the generation and regulation of cardiac rhythm. Accordingly, the right atrium exhibited the most specific signature, whereas the majority of GPCRs found in ventricles were evenly expressed in both the right and left chambers. RT-PCR data were confirmed at the protein level for six selected transcripts. Furthermore, we provide new data showing that, as suggested by our repertoire, the metabotropic glutamate receptor 1b is expressed and is functional in ventricular cardiac myocytes. This is the first report describing GPCRs in the four cardiac chambers and may assist in the identification of therapeutic targets.The four cardiac chambers display morphological and functional differences. They can be distinguished on the basis of contractile properties, rhythm generation, and response to neurohumoral stimulation (Brown et al., 1991;Barth et al., 2005;Narolska et al., 2005). Contractile activity of the heart ensures that blood flow is adapted to the needs of the organism. Left ventricular performance depends on the chamber's capacity to fill up (diastolic property) and to empty (systolic property), and these properties are altered in pathological conditions, the final consequence being heart failure. To trigger the contractile activity, cardiac automaticity is generated by a set of specialized pacemaker cells forming the sinoatrial node (SAN) (Mangoni and Nargeot, 2008). Compared with myocytes of the working myocardium, pacemaker SAN cells are devoted to the generation of an electrical oscillation rather than having a contractile activity. At the molecular level, heart chamber heterogeneity is reflected by the expression patterns of different sets of genes such as transcription factors (Tabibiazar et al., 2003) and ion channels (Marionneau et al., 2005). The heart expresses GPCRs (Regard et al.,

Cardiovascular Actions of Incretin-Based Therapies

“…10 A novel mouse monoclonal antibody localized immunohistochemical GLP-1R expression to the atria, but not the ventricle, predominantly within the sinoatrial node, in monkey and human heart tissue. 9 Taken together, these findings are consistent with an earlier report describing Glp1r expression in the right and left atria, but not the ventricle, of the mouse heart, 17 although low levels of Glp1r expression in noncardiomyocyte cell types within the ventricles, in blood vessels, fibroblasts, immune cells, or nerves, cannot be excluded.…”

Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system

“…Studies in other fields, mainly developmental biology, suggest that this is not a specialty of GPCRs, but is also observed in other gene families1718. These findings have major implications for pharmacotherapy, since current interpretations of GPCR expression data rely on the assumption that all cells of a given population are equal, or at least comparable15163031. Our data not only clearly disprove this assumption for the majority of GPCRs, they also open up the possibility to selectively target pathologically altered cells based on their specific GPCR repertoire.…”

Genome-wide profiling of G protein-coupled receptors in cerebellar granule neurons using high-throughput, real-time PCR

“…To illustrate the usefulness of the high throughput PCR approach, we and others performed tissue profiling, which gives a static view of the GPCR repertoire in a mixture of cell types [8,19]. In the present work, we focused on a more dynamic setting, and monitored the remodeling of the GPCR repertoire in a single neuronal subtype.…”