B1 Bradykinin Receptors and Carboxypeptidase M Are Both Upregulated in the Aorta of Pigs after LPS Infusion

Tan

Journal of Biological Chemistry

et al. 2008

Kinin B1 receptor (B1R) expression is induced by injury or inflammatory mediators, and its signaling produces both beneficial and deleterious effects. Kinins cleaved from kininogen are agonists of the B2R and must be processed by a carboxypeptidase to generate B1R agonists des-Arg 9 -bradykinin or desArg 10 Carboxypeptidase M (CPM) 2 was discovered as a glycosylphosphatidylinositol (GPI)-anchored membrane protein with B-type carboxypeptidase activity (1-3) and is a member of the "regulatory" or carboxypeptidase N/E subfamily of metallocarboxypeptidases (4 -8) based on its cDNA sequence (9), genomic structure (10), and x-ray crystal structure (11). The overall structure of CPM is composed of a 295-residue N-terminal catalytic domain, followed by an 86-residue conical ␤-sandwich (transthyretin-like domain) and a unique 25-residue extension to which the GPI anchor is post-translationally attached (11).CPM cleaves only C-terminal Arg or Lys residues, and some of its endogenous substrates include bradykinin, anaphylatoxins C3a, C4a, and C5a, Arg-or Lys-enkephalins, epidermal growth factor, and hemoglobin (2, 7, 12, 13). CPM preferentially cleaves C-terminal Arg as exemplified by the kinetics with Arg 6 -Met 5 -enkephalin (K m ϭ 46 M, k cat ϭ 934 min Ϫ1 ) versus Lys 6 -Met 5 -enkephalin (K m ϭ 375 M, k cat ϭ 663 min Ϫ1 ) (2). Bradykinin exhibits the lowest K m (16 M) of any CPM substrate tested (2), a concentration that is still much higher than the typical physiological concentration of this peptide in the nanomolar range. However, peptidases in vivo typically work at substrate concentrations far below the K m as exemplified by angiotensin I-converting enzyme (ACE), which has the same relatively high K m (16 M) with angiotensin I (14), a major physiological substrate. The development of ACE inhibitors as effective agents for treating hypertension and cardiovascular diseases was based in large part on the critical role of this enzyme in converting angiotensin I to II in vivo (15).The kinin peptides bradykinin and kallidin (Lys-bradykinin) are generated by the proteolytic action of plasma or tissue kallikrein on high or low molecular weight kininogen (16,17). Removal of the C-terminal Arg from bradykinin or kallidin inactivates these peptides as agonists of the constitutively expressed B2 receptor (B2R) (16,17). However, this conversion is a required processing step to generate desArg 9 -bradykinin or des-Arg 10 -kallidin (16, 18), metabolites that have a variety of biological activities mediated by specific activation of a different B1 receptor (B1R) whose expression is induced by inflammatory mediators (19,20). Thus, CPM acts as a cell surface processing enzyme to generate des-Arg-kinin agonists for the B1R, and without this catalytic conversion, B1R signaling could not occur. This is of potential importance in inflammatory or pathological responses. For example, B1R activation stimulates extracellular signal-regulated kinase phosphorylation, prostaglandin production (20), and inducible nitric-oxide synthase-mediate...

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Tan

Journal of Biological Chemistry

et al. 2008

“…Kinins are potent vasodilator oligopeptides that contain the nonapeptide bradykinin [BK- (1)(2)(3)(4)(5)(6)(7)(8)(9)] as part of their sequence. Kinins have effects on many different aspects of physiology, including the regulation of blood pressure and of renal and cardiac function, and have been implicated in the pathogenesis of hypertension and inflammation (for a review, see 1).…”

Section: Introductionmentioning

confidence: 99%

“…The B 2 receptor normally predominates, whereas B 1 receptors are induced by tissue injury, such as that which occurs following myocardial ischaemia (2) and inflammation (3). A complex variety of kinin peptides acts through these receptors.…”

Section: Introductionmentioning

confidence: 99%

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

2000

Braz J Med Biol Res

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikreinkinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikreinkinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

Journal of Biological Chemistry

“…Evidence for an Allosteric Interaction between CPM and B1R in Primary Cells-CPM is present in human endothelial cells, and inflammatory cytokines can increase its expression 2-3-fold, conditions that also up-regulate B1R expression (6,14,(31)(32)(33)52). We thus used cytokine-treated HLMVEC to examine the allosteric effect of CPM on B1R function.…”

Section: Extracellular Loop 2 Of the B1r And A Cpm C-terminal Domain mentioning

confidence: 99%

“…CPM has ideal properties in this regard, being a GPI-anchored plasma membrane protein with a neutral pH optimum exhibiting a specificity for C-terminal Arg and the lowest K m for BK of the physiological substrates tested (1,8,12,30). In addition to its wide distribution, endotoxin or cytokines that induce B1R expression (14) also increase CPM expression (31)(32)(33). Thus, it is likely that cells expressing B1Rs also express CPM.…”

mentioning

confidence: 99%

Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Zhang¹,

Tan

Skidgel

2013

Background: Carboxypeptidase M (CPM) generates agonist for the kinin B1 receptor (B1R). Results: CPM binds to B1R on the cell membrane and allosterically increases B1R agonist affinity. Conclusion: CPM is a positive allosteric modulator of the B1R, thereby increasing receptor signaling. Significance: Interfering with CPM binding to B1R could be a novel approach to inhibit deleterious effects of B1R signaling in inflammation.