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_Dr. Mohr's lectures_kinins[1].lecture.04

_Dr. Mohr's lectures_kinins[1].lecture.04 - Kinins Overview...

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Factor  XII Factor  XIIa Plasma  prekallikrein Plasma  kallikrein HMW  kininogen Bradykinin Inactive peptides Kininases Contact with negative charged surface FXI T p issue rokallikrein Tissue kallikrein Kallidin LMW  kininogen ? - - - - - - - - - - - - - - - - - Kinins Overview: Two activation system have been described— Contact System and Endothelial Receptor System Contact System
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Receptor HK PK/FXI PK/FXI Intact endothelial cell membrane FXII HK Receptor HKa K/FXI BK Endothelial cell membrane Serine protease Receptor HKa K/FXI FXIIa A. B. C. Overview: Endothelial Cell Receptor System Zn 2+ Intact endothelial cell membrane; also platelet and granulocyte membranes FXIIa
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3 Kallikreins Two forms—Plasma and Tissue Differ in MW, substrate specificity, type of kinin released, functional importance Acidic glycoproteins Serine proteases (kininogenases) Found in biological fluids, glandular tissues, neutrophils HMW  kininogen LMW  kininogen Plasma  pre-kallikrein Tissue  kallikrein Ka llid in Plasma  kallikrein Br a d y k inin
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4 Plasma kallikrein Plasma kallikrein, single gene Synthesized as a zymogen (prekallikrein) in the liver Prekallikrein circulates bound to HMW kininogen and Factor XI (Plasma Thromboplastic Antecedent) Kallikrein from action of FXII or binding to HMW K? Formation of kallikrein requires zinc (1-4 μM) Plasma kallikrein cleaves bradykinin from HMW kininogen Major substrate for PK is High Molecular Weight Kininigen (HMK); also LMW kininogen but less preferred Plasma kallikreins are rapidly inactivated by C1- Inhibitor, a 2 -macroglobulin, and antithrombin III
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5 Tissue kallikrein Tissue kallikrein, multiple gene family Formed first as zymogen: prokallikrien Tissue kallikrein forms kallidin (Lys-bradykinin) from LMW kininogen (preferred) and HMW kininogen Some conversion of kallidin to bradykinin may occur by the action of aminopeptidases Tissue kallikrein gene found in epithelial and secretory cells of ducts Salivary, sweat, pancreatic , prostatic, intestinal, and distal nephron, endothelium Tissue kallikrein mRNA found in cultured vascular smooth muscle and in neutrophils
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6 Tissue kallikrein Several proteases in vitro can activate tissue kallikrein from prokallikrein The in vivo activating enzyme is not known Inhibitors of tissue kallikrein Aprotinin, bovine basic pancreatic trypsin inhibitor, kallistatin Roles in angiogenesis, organogenesis, apoptosis, proliferation T p issue rokallikrein Tissue kallikrein Kallidin LMW  kininogen ?
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7 Roles for kallikreins Pl  Kallikrein Pro-Urokinase Urokinase Plasmin Plasminogen Ka llikr e ins Act ivat ion  of
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