International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Leeb-Lundberg, L.M. Fredrik; Marceau, François; Müller‐Esterl, Werner; Pettibone, Douglas J.; Zuraw, Bruce L.

doi:10.1124/pr.57.1.2

Cited by 883 publications

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References 521 publications

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“…The actions of bradykinin or kallidin (Lys-bradykinin) are mediated via activation of the B2 receptor which is critically dependent on the presence of the C-terminal arginine [63]. However, des-Arg 9 -bradykinin or des-Arg 10 -kallidin generated by CPN has a variety of activities mediated through a different receptor designated "B1" [64,65]. The B1 receptor system is upregulated in response to injury or inflammatory mediators and may be part of the acute phase reaction [63,65].…”

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

“…However, des-Arg 9 -bradykinin or des-Arg 10 -kallidin generated by CPN has a variety of activities mediated through a different receptor designated "B1" [64,65]. The B1 receptor system is upregulated in response to injury or inflammatory mediators and may be part of the acute phase reaction [63,65]. Thus, conversion of kinins to des-Arg-kinins to produces the endogenous agonists for the B1 receptor, of potential importance in inflammatory or pathological responses.…”

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

“…Thus, conversion of kinins to des-Arg-kinins to produces the endogenous agonists for the B1 receptor, of potential importance in inflammatory or pathological responses. Activation of B1 receptors initiates increased ERK activation, prostaglandin production [65], high output NO generation and inhibits PKCε activity in cytokine-treated human endothelial cells [66][67][68].…”

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

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Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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Human carboxypeptidase N (CPN) was discovered in the early 1960s as a plasma enzyme that inactivates bradykinin and was identified 8 years later as the major "anaphylatoxin inactivator" of blood. CPN plays in important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. This review summarizes the structure, enzymatic properties and function of this important human enzyme, including insights gained by the recent elucidation of the crystal structure of the CPN catalytic subunit and structural modeling of the non-catalytic regulatory 83 kDa subunit. We also discuss its physiological role in cleaving substrates such as kinins, anaphylatoxins, creatine kinase, plasminogen receptors, hemoglobin and stromal cell-derived factor-1α (SDF-1α). HistoryCarboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue. (Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN. This finding explains our interest in the work of Dr. Tony Hugli, who has made many seminal contributions to the understanding of the structure and function of anaphylatoxins [24][25][26][27]. In Send Correspondence and Proofs To: Randal A. Skidgel, PhD, Dept. of Pharmacology (M/C 868), Univ. of Illinois College of Medicine, 835 S. Wolcott, Chicago, IL 60612, Phone: 312-996-9179, FAX: 312-996-1648, EMAIL: E-mail: rskidgel@uic.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript w...

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Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

Section: Hydrolysis Of Biologically Relevant Peptides In Vivomentioning

confidence: 99%

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Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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“…The effects of kinins on target cells are linked to 2 subtypes of kinin receptors, the B1 receptor and the B2 receptor (10,13,14). B2 receptors are expressed constitutively in many different cell types, whereas B1 receptors are induced during inflammatory conditions (14,15).…”

mentioning

confidence: 99%

“…B2 receptors are expressed constitutively in many different cell types, whereas B1 receptors are induced during inflammatory conditions (14,15). The relative importance of signaling through the B1 and B2 receptors in vivo is not known, but it has been suggested that B1 receptors may be particularly important in inflammatory conditions, not only because of their induction but also due to the fact that des-Arg metabolites of BK and kallidin, acting preferentially on B1 receptors, are produced in inflammatory processes by carboxypeptidases.…”

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confidence: 99%

Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

Brechter¹,

Lerner²

2007

Arthritis & Rheumatism

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Objective. Bradykinin (BK) stimulates bone resorption in vitro and synergistically potentiates interleukin-1 (IL-1)-induced bone resorption and prostaglandin (PG) formation, suggesting that kinins are important in inflammation-induced bone loss. The present study was undertaken to study 1) the role of the kinin B1 and B2 receptors in the synergistic interaction with IL-1 and tumor necrosis factor ␣ (TNF␣), 2) the molecular mechanisms involved in synergistic enhancement of PG formation, and 3) the effects of kinins on cytokine-induced expression of RANKL, RANK, and osteoprotegerin (OPG) (the latter being crucial molecules in osteoclast differentiation).Methods. Formation of PGs, expression of enzymes involved in arachidonic acid metabolism, and expression of RANKL, RANK, and OPG were assessed in the human osteoblastic cell line MG-63 and in mouse calvarial bones.

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Endogenous Vasoactive Peptides

Webb

Ksander²

2010

Burger's Medicinal Chemistry and Drug Discovery

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The control of vasomotor tone regulates the overall cardiovascular system and its responses to physiological and pathophysiological stress. It provides differential blood flow to regional vascular beds under normal physiologic conditions, at times of normal stress, such as exercise, and during conditions of pathological stress, such as congestive heart failure. Although the vascular system regulates many of its functions at the site of the blood vessel itself, other factors that may control vascular tone include the autonomic nervous system, circulating hormones functioning in an endocrine role, and reflex metabolic control. Many newly discovered peptides were found to be widespread in autonomic and sensory neurons innervating the vasculature, and they possess potent vasoactive effects on many blood vessels. Vasoactive peptides have been shown to play an important role in many pathological situations, for example, asthma, arthritis, vascular headaches, hypertension, and other cardiovascular diseases. In this chapter, we will outline the evidence for the different actions of various vasoactive peptides, their interaction with other systems, the possible role they have in diseases, and the present and future therapeutic use of vasoactive peptide agonists and antagonists.

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International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Cited by 883 publications

References 521 publications

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

Endogenous Vasoactive Peptides

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