Novel bitter taste receptor ligands elicit G protein‐dependent negative inotropic effects in mouse heart (LB572)

Abstract

G protein‐coupled receptors (GPCRs) are key mediators in cardiovascular physiology, yet frontline therapies for heart disease only target a small fraction of the cardiac GPCR repertoire. Moreover, there is emerging evidence that GPCRs implicated in taste (TIR and T2Rs) have specific functions beyond the oral cavity. Our recent description of these receptors in heart foreshadows a novel role for previously unappreciated cardiac GPCRs. Here, we sought to identify novel ligands for cardiac‐T2Rs and investigate their effects on murine cardiac function ex vivo. Five T2Rs cloned from rat heart, were screened against a panel of 102 natural or synthetic bitter chemicals in a heterologous expression system. After validating putative T2R ligands for receptor and concentration‐dependence, three novel ligands for T2R108, T2R137 and T2R143 were then tested in Langendorff perfused mouse hearts (isolated from 8 week old male C57BL/6 mice). All T2R ligands tested exhibited concentration‐dependent effects on cardiac function. Furthermore, the biphasic change of aortic pressure with sodium benzoate and the ~40% sodium thiocyanate‐mediated decrease in left ventricular developed pressure were both abrogated in the presence of Gαi and Gβγ inhibitors (pertussis toxin, 100 µg/kg i.p. 24 hr prior to isolation and gallein, 10 µM infusion, respectively). This study represents the first demonstration of profound T2R ligand‐induced, G protein‐dependent effects on mouse heart function. Future work will focus on the delineation of specific receptor‐dependent responses of these ligands.Grant Funding Source: Supported by Australian National Health and Medical Research Council (NHMRC) (1024726) and the National Heart Foundation of Australia (G‐12B‐6532)