Carboxypeptidase M augments kinin B1 receptor signaling by conformational crosstalk and enhances endothelial nitric oxide output

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins that play key roles in transducing extracellular signals to intracellular proteins to generate cellular responses. The kinin GPCRs, named B1 (B1R) and B2 (B2R) are responsible for mediating the biological responses to kinin peptides released from the precursor kininogens. Bradykinin or kallidin are agonists for B2Rs whereas their carboxypeptidase-generated metabolites, des-Arg9-bradykinin or des-Arg10-kallidin are specific agonists for B1Rs. Here we review the evidence for a critical role of membrane-bound carboxypeptidase M in facilitating B1R signaling by its ability to directly activate the receptor via conformational crosstalk as well as generate its specific agonist. In endothelial cells, the carboxypeptidase M/B1R interaction facilitates B1R-dependent high output nitric oxide under inflammatory conditions.