id: PW:0000526 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000526 title: kallikrein-kinin cascade pathway description: 'Kallikrein-kinin (KKS) cascade pathway leads to the production of active kinin peptides whose signaling via two G-protein coupled (GPCR) receptors prompts a range of responses that include vasodilation, release of inflammatory mediators, stimulation of sensory neurons. Recent studies also point to a potential role in oxidative stress. All active peptides are derived from a single precursor - kininogen (Kng1). Alternative splicing of Kng1 gives rise to the high- and low-molecular weight kininogens (HK and LK). Their processing by plasma and tissues serine proteases Klkb1 and Klk1, respectively, gives rise to two active peptides: the nonapeptide bradykinin (BK) and the decapeptide kallidin (KD). The two enzymes are known as kallikreins. Further C-terminal processing of these peptides by carboxypeptidase M (Cpm) and N (Cpn1) gives rise to the des-Arg metabolites. Other kinin metabolites are also produced but so far, they have only been reported in rat. The plasma kallikrein Klkb1, is secreted from the liver as an inactive prekallikrein which circulates bound to HK and whose activation is carried out by an activated factor XII, known as Hageman factor - F12a. The contact of plasma with a negative surface leads to binding and autoactivation of F12 which in turn activates prekallikrein - a first step in the kallikrein-kinin cascade and also in the coagulation cascade. F12a can also stimulate the classical complement pathway. Active Klkb1 cleaves HK in a two-step reaction to produce BK. It also further activates F12 whose initial conformational changes induced by contact only produce small amounts of F12a, thus providing a positive feedback loop. Prolylcarboxypeptidase (Prcp) can also activate prekallikrein, in addition to other substrates. Several inhibitors of F12 and Blkb1 are known with Serping1, known as C1INH being the principal regulator. Serping1 and alpha2-macroglobulin (A2m), account for more than 90% of Klkb1 inhibitory activity. The tissue kallikrein Klk1 is widely distributed and while it primarily cleaves LK to form KD, it may also cleave HK. The regulatory mechanisms of tissue kallikrein are less well characterized; Serpina4, known as kallistatin and found in several tissues and cell types, is a Klk1 inhibitor. The peptides are metabolized to inactive compounds by several kininases of which some are shared with the renin-angiotensin system, such as Ace and Mme. There, they act as angiotensinases converting the inactive angiotensin I to the potent AgtII and to Agt1-7, respectively. In the kallikrein-kinin system the enzymes act as kininases. Others include aminopeptidase P which has both a soluble (Xpnpep1) and a membrane-bound (Xpnpep2) form and both can hydrolyze the kinins to inactive metabolites. The human cytoplasmic XPNPEP1 uses Mn2+ at the active site, whereas the membrane-bound XNPEP2 uses Zn2+. Zn2+, used by most other proteases, inhibits XPNPEP1. Two bradykinin receptors - Bdkrb1 and Bdkrb2 - convey the signals of active kinins. Both receptors are G-protein coupled (GPCR) that stimulate phospholipase activity, increase intracellular calcium concentration and prompt the release of several compounds such as nitric oxide, arachidonic acid, prostaglandins and other inflammatory mediators. Of the two receptors, receptor type 2 is ubiquitously expressed and type 1 is inducible. BK and KD are the agonists of receptor type 2; the carboxy-terminal derived des-Arg peptides are the agonists of receptor type 1. Several antagonists have been developed for both receptors; first generation and second generation antagonists and third generation non-peptides compounds. Other kinin antagonists have been discovered as natural compounds.' diagram_image: https://rgd.mcw.edu/pathway/PW0000526/kallikrein-kinin%20cascade%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000526/kallikrein-kinin%20cascade%20pathway/kallikrein-kinin%20cascade%20pathway.gpp diagram_pathway_links: - id: PW:0000474 label: coagulation cascade pathway - id: PW:0000503 label: classical complement pathway - id: PW:0001480 label: kinin signaling pathway diagram_gene_links: - id: RGD:2004 label: A2m - id: RGD:620401 label: Bdkrb1 - id: RGD:2201 label: Bdkrb2 - id: RGD:1310532 label: Cpm - id: RGD:70931 label: Cpn1 - id: RGD:2980 label: des-Arg-kinins - id: RGD:1359175 label: F12a - id: RGD:2969 label: Klk1 - id: RGD:67382 label: Klkb1 - id: RGD:1307842 label: Prcp - id: RGD:708581 label: Serpina4 - id: RGD:735225 label: Serping1 diagram_chemicals: [] diagram_edges: - source: A2m relation: negatively_affects target: Klkb1 - source: BK relation: positively_affects target: des-Arg-kinins - source: BK relation: positively_affects target: inactive kinins - source: BK relation: positively_affects target: inflammatory mediators release - source: BK relation: positively_affects target: sensory neuron stimulation - source: BK relation: positively_affects target: vasodilation - source: Bdkrb1 relation: associated_with target: des-Arg-kinins - source: Bdkrb2 relation: associated_with target: BK - source: Bdkrb2 relation: associated_with target: KD - source: KD relation: positively_affects target: des-Arg-kinins - source: KD relation: positively_affects target: inactive kinins - source: KD relation: positively_affects target: inflammatory mediators release - source: KD relation: positively_affects target: sensory neuron stimulation - source: KD relation: positively_affects target: vasodilation - source: Kng1 relation: positively_affects target: highKng1 - source: Kng1 relation: positively_affects target: lowKng1 - source: Serpina4 relation: negatively_affects target: Klk1 - source: Serping1 relation: negatively_affects target: F12a - source: Serping1 relation: negatively_affects target: Klkb1 - source: des-Arg-kinins relation: positively_affects target: inactive kinins - source: des-Arg-kinins relation: positively_affects target: inflammatory mediators release - source: des-Arg-kinins relation: positively_affects target: sensory neuron stimulation - source: des-Arg-kinins relation: positively_affects target: vasodilation - source: highKng1 relation: associated_with target: pKlkb1 - source: highKng1 relation: positively_affects target: BK - source: lowKng1 relation: positively_affects target: KD diagram_labels: - F12 --+> F12a - F12a --+> classical complement pathway - F12a --+> coagulation cascade pathway - F12a --+> Klkb1 - inactive kinins - inflammatory mediators release - Klkb1 --+> F12a - Prcp --+> Klkb1 - sensory neuron stimulation - vasodilation diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/kininases label: kininases references: - id: RGD:7401223 citation: Moreau ME, etal., J Pharmacol Sci. 2005 Sep;99(1):6-38. - id: RGD:7401224 citation: 'Mallela J, etal., Int J Biochem Cell Biol. 2009 Mar;41(3):477-81. doi: 10.1016/j.biocel.2008.02.022. Epub 2008 Feb 29.' - id: RGD:7401225 citation: Leeb-Lundberg LM, etal., Pharmacol Rev. 2005 Mar;57(1):27-77. - id: RGD:7411615 citation: 'Maas C and Renne T, Thromb Res. 2012 May;129 Suppl 2:S73-6. doi: 10.1016/j.thromres.2012.02.039. Epub 2012 Mar 6.' - id: RGD:7411616 citation: 'Chao J, etal., Biol Chem. 2010 Apr;391(4):345-55. doi: 10.1515/BC.2010.042.' - id: RGD:7411617 citation: 'Hillmeister P and Persson PB, Acta Physiol (Oxf). 2012 Dec;206(4):215-9. doi: 10.1111/apha.12007.' - id: RGD:7411618 citation: 'Kaplan AP and Joseph K, Ann Allergy Asthma Immunol. 2010 Mar;104(3):193-204. doi: 10.1016/j.anai.2010.01.007.' - id: RGD:7411619 citation: 'Kaplan AP and Ghebrehiwet B, Mol Immunol. 2010 Aug;47(13):2161-9. doi: 10.1016/j.molimm.2010.05.010.' - id: RGD:7411620 citation: 'Tomita H, etal., Kidney Int. 2012 Apr;81(8):733-44. doi: 10.1038/ki.2011.499. Epub 2012 Feb 8.'