Abstract
The 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 (BK) or kallidin (KD) are agonists for B2Rs, whereas their carboxypeptidase (CP)-generated metabolites, des-Arg(9)-BK or des-Arg(10)-KD, are specific agonists for B1Rs. Here, we review the evidence for a critical role of membrane-bound CPM 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 CPM/B1R interaction facilitates B1R-dependent high-output nitric oxide under inflammatory conditions.
Highlights
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
Most of these proteins interact with the intracellular domains of GPCRs, but some membrane proteins can interact with GPCRs and regulate their function
We found that B1R stimulation of cytokine-treated human lung microvascular endothelial cells (HLMVEC) led to even higher and more prolonged nitric oxide (NO) output than B2R, but in contrast to the B2R response, it was mediated through acute activation of iNOS and not eNOS (Ignjatovic et al, 2004; Zhang et al, 2007)
Summary
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. This function is more likely carried out by membrane-bound peptidases with extracellular active sites, where local cleavage of peptide agonists regulates their levels at or near their cognate receptors. HEK cells stably expressing B1Rs alone did not respond to 1 μM KD, but exhibited a robust increase in [Ca2+]i in response to 1 μM des-Arg10-KD (DAKD), the B1R agonist (Fig. 2A).
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