Bradykinin缓激肽PPT 原创

1、Bradykininf fLee Liyli29qub.ac.uk& its G-protein-coupled receptorsObjectivesSynthesis MetabolismPhysiological rolesOf bradykininand its receptorsClassificationMechanismGPCR signallingWhat bradyininiLocal hormoneVasodilation(扩张血管)Lowering Lowering blood blood pressurepressureArg-Pro-Pro-Gly-Phe-S

2、er-Pro-Phe-ArgPeptideBioactiveSynthesis in vivoThe formation of bradykinin in vivo consists of two distinct pathways: the plasma bradykinin-forming cascade & & the tissue pathwayThe kinin-kallikrein system(激肽释放酶-激肽系统) makes bradykinin by proteolytic（ 蛋白水解 ） cleavage of its kininogen（ 激肽原 ） p

3、recursor by the enzyme kallikrein.kinin-kallikrein system in plasmaSynthesis in vivoFigure: the plasma bradykinin-forming cascadeBradykininHMW kininogen kallikreinprekallikreinFactor XIIaFactor XIIInhibited by C1 INH (C1酯酶抑制物)angiotensin-converting enzyme (ACE ) carboxypeptidase M (CPM) aminopeptida

4、se P bradykininACEheptapeptidePhe-argACESer-propentapeptide CPMbradykininDes-arg-9 bradykininArgMetabolism of BradykininB1 receptor and the B2 receptorG-protein coupled receptorsBradykinin Receptors The 2012 Nobel Prize in Chemistry was awarded to for their work that was crucial for understanding ho

5、w G-proteincoupled receptors function.Brian Kobilka Robert Lefkowitz ？What are G-proteincoupled receptorsWhy are they so importantAwesome! But waitConstitute a large protein family of receptorsSense molecules outside the cell Activate inside signal transduction pathways and cellular responses. WhatG

6、 protein-coupled receptors are the target of approximately 40% of all modern medicinal drugsAmong the top 50 best-selling drugs, 20% of belong to the G protein receptor drugs4020/50WhyHowFirst messengersSecond messengersligandsHow Hormones Use G-protein Signalling Pathwayshormones use G protein coup

7、led receptor signalling pathwayEncoded by BDKRB1 gene in humansBinding results in chronic and acute inflammatory responses（炎症反应）Endocytosed and degraded12345B1Preferentially bound by des-Arg9-bradykininSynthesized de novo following tissue injuryADCBBDKRB2 gene in humansPreferentially boundby bradyki

8、nin Phosphorylated by a GPCR kinase and recruit b-arrestinIt is ubiquitously and constitutively expressed in healthy tissuesB2EncodedPreferenceMetabolismExpressionB2BKR-2BradykininPositive effectsNegative effectsBronchospasm-Acute pain/Inflammation-Hyperalgesia-Vascular hyperpermeabilityCoughAngioed

9、ema-Release of NO,PGI2 and EDHF-Stimulation of tPA-Inhibition of thrombin-Anrtiischemia-Antiproliferation-AntihypertrophiaCardiovascular protectionPhysiological roles ofOptimal B2 receptor antagonists should compete with bradykinin to prevent receptor signalling. Conversely, as well as competitive binding, optimal B1 receptor antagoni