The kallikrein-kinin (KKS) cascade pathway generates the active kinin peptides. Kinin signaling plays important roles in the cardiovascular, renal, respiratory and nervous systems. It elicits vasodilator, inflammatory and pain responses and it exert both proliferating and anti-proliferating effects. The active kinin peptides bradykinin (BK), kallidin (KD) and their C-terminal processed des-Arg-metabolites signal via two G-protein coupled (GPCR) receptors, known as B1R and B2R, encoded by Bdkrb1
and 2, respectively. Receptor type 2 is ubiquitously expressed whereas type 1 is inducible. Bradykinin (BK) and kallidin (KD) are the preferred agonists of receptor type 2; their des-Arg-metabolites are the preferred agonists of receptor type 1. Both receptors couple to Galphai and Galphaq types of heterotrimeric G protein alpha subunits and can also signal independent of G proteins. Both trigger the activation of phospholipase B, the generation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), the latter prompting the release of calcium from intracellular stores. DAG and calcium, separately or together stimulate protein kinase C (PKC) signaling which activates the Erk1/2 MAP kinase cascade. Via increased calcium concentration, the receptors stimulate nitric oxide (NO) synthase activities and NO production, phospholipase A2 stimulation and the production of arachidonic acid, prostaglandins and other inflammatory mediators, along with the pathways these molecules initiate. The receptors are subject to several types of post-translational modifications such as glycosylation and acylation and also phosphorylation; the latter also plays an important role in receptor desensitization. In addition to the Galpha subunits, the classical components of G protein signaling, the Gbeta/dimer, released upon GPCR activation, may also play a role in kinin mediated signaling. G alpha are active in the GTP-bound state and inactive in the GDP-bound state. The activated GPCR act as G protein exchange factors (GEF), that promote the release of GDP and binding of GTP and the subsequent release of activated Galpha subunit which now can activate its own effectors. G protein kinases (GRK) phosphorylate activated receptors which are then recognized by arrestin proteins whose binding precludes the re-association with G proteins thus inducing the desensitization of GPCRs. Of the many GRKs involved in GPCRs desensitization, Grk4 is the one involved in the kinin receptors mediated pathways. Although the two receptors appear to couple to similar intracellular signaling pathways, there is nonetheless a distinction between their signaling modes. Receptor type 1 is induced under certain conditions, is not significantly phosphorylated, is desensitized to a limited degree, appears to have a different distribution in the plasma membrane and is not significantly internalized; in addition, it does not appear to be present in sensory neurons. Several polymorphisms have been described for both receptors of which some have been associated with pathophysiological conditions. To see the ontology report for Gviewer, annotations and download, click here ...(less)
