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

Zhang, Xianming; Tan, Fulong; Skidgel, Randal A.

doi:10.1074/jbc.m113.520791

Cited by 26 publications

(18 citation statements)

References 72 publications

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“…These included CPM, which has a potential role in cell signaling and tissue remodeling [43][44][45]; MME, a stroma-specific protein used in determining the pathologic diagnosis of endometrial stromal sarcoma as opposed to other sarcoma [46][47][48]; and ENPP3, in which we noted strong uterine expression in the Human Protein Atlas resource [49][50][51]. Ectonucleotide pyrophosphatase/phosphodiesterase 3, a member of a family of proteins with ATPase activity involved in the hydrolysis of extracellular nucleotides, is a transmembrane protein classed with other cell-surface ectoATPases that modulate complex interactions with nucleotides and their breakdown products [52][53][54].…”

Section: Proteomics Of the Premenopausal Endometriummentioning

confidence: 99%

Proteomics of the Human Endometrial Glandular Epithelium and Stroma from the Proliferative and Secretory Phases of the Menstrual Cycle1

Hood

Liu

Alkhas

et al. 2015

Biology of Reproduction

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Despite its importance in reproductive biology and women's health, a detailed molecular-level understanding of the human endometrium is lacking. Indeed, no comprehensive studies have been undertaken to elucidate the important protein expression differences between the endometrial glandular epithelium and surrounding stroma during the proliferative and midsecretory phases of the menstrual cycle. We utilized laser microdissection to harvest epithelial cells and stromal compartments from proliferative and secretory premenopausal endometrial tissue and performed a global, quantitative mass spectrometry-based proteomics analysis. This analysis identified 1224 total proteins from epithelial cells, among which 318 were differentially abundant between the proliferative and secretory phases (q < 0.05), and 1005 proteins from the stromal compartments, 19 of which were differentially abundant between the phases (q < 0.05). Several proteins were chosen for validation by immunohistochemistry in an independent set of uterine tissues, including carboxypeptidase M, tenascin C, neprilysin, and ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3). ENPP3, which was elevated in epithelial glandular cells in the secretory phase, was confirmed to be elevated in midsecretory-phase baboon uterine lavage samples and also observed to have an N-linked glycosylated form that was not observed in the proliferative phase. This study provides a detailed view into the global proteomic alterations of the epithelial cells and stromal compartments of the cycling premenopausal endometrium. These proteomic alterations during endometrial remodeling provide a basis for numerous follow-up investigations on the function of these differentially regulated proteins and their role in reproductive biology and endometrial pathologies.

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Section: Proteomics Of the Premenopausal Endometriummentioning

confidence: 99%

Proteomics of the Human Endometrial Glandular Epithelium and Stroma from the Proliferative and Secretory Phases of the Menstrual Cycle1

Hood

Liu

Alkhas

et al. 2015

Biology of Reproduction

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“…CPM is a largely distributed enzyme that cleaves C-terminal lysine or arginine from other peptides and proteins, including anaphylatoxins, chemokines, enkephalins and growth factors (Deiteren et al, 2009 ) that may question its specificity as a pharmacological target. While the regulatory role of CPM in kinins and B1R activity has been fairly well documented (Erdos and Sloane, 1962 ; Zhang et al, 2013a , b ; Couture et al, 2014 ; Regoli and Gobeil, 2015 ), the impact of CPM on the physiological functions of other endogenous substrates, and particularly in insulin resistance, is still unknown and remains to be studied. In the present study, the inhibition of B1R-agonists formation by Mergetpa has not been directly demonstrated and is not an easy task in vivo due to the short life of these peptides, but the impact of CPM blockade is in accordance with the beneficial effects of B1R antagonism in insulin resistance and its associated oxidative stress and inflammatory mechanisms (Dias et al, 2010 ; Dias and Couture, 2012b ; Haddad and Couture, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to generating B1R agonists in close proximity to the receptor, biochemical studies in transfected cells suggest that CPM interacts with the B1R to enhance B1R signaling. Kinin (BK or kallidin) binding to the CPM active site causes a conformational activation of the B1R (Zhang et al, 2013a ) and basal binding of CPM to extracellular loop 2 of the B1R results in positive allosteric modulation of B1R signaling to its orthosteric agonist (Zhang et al, 2013b ). Recently, CPM and B1R were found upregulated along with the inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) in aorta, renal cortex and liver in a rat model of insulin resistance induced by high glucose feeding (Haddad and Couture, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Kininase 1 As a Preclinical Therapeutic Target for Kinin B1 Receptor in Insulin Resistance

Haddad

Couture

2017

Front. Pharmacol.

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Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kininase 1 (carboxypeptidase M, CPM), the key enzyme involved in the biosynthesis of B1R agonists, could exert the same beneficial effects to B1R antagonism in insulin resistance. Male Sprague-Dawley rats were made insulin resistant with a drinking solution containing 10% D-glucose for a period of 9 weeks. Control rats received tap water. During the last week, kininase 1 was blocked with Mergetpa (1 mg kg−1 twice daily, s.c.) and the impact was determined on insulin resistance (HOMA index), metabolic hormone levels, oxidative stress and the expression of several markers of inflammation by western blot and qRT-PCR. Glucose-fed rats displayed hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin resistance, hypertension, positive body weight gain, and enhanced expression of B1R, CPM, iNOS, and IL-1β in renal cortex, aorta and liver. Markers of oxidative stress (superoxide anion and nitrotyrosine expression) were also enhanced in aorta and renal cortex. Mergetpa reversed and normalized most of those alterations, but failed to affect leptin levels and hypertension. Pharmacological blockade of kininase 1 (CPM) exerted similar beneficial effects to a 1-week treatment with a B1R antagonist (SSR240612) or an iNOS inhibitor (1,400 W). These data reinforce the detrimental role of B1R in insulin resistance and recommend CPM as a new therapeutic target.

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“…Our studies have identified a critical complex in lipid raft microdomains between kB1R and CPM, the enzyme that generates its agonist (8, 9). This kB1R/CPM heterodimer facilitates kB1R signaling in three ways (8, 9, 64, 65): 1) Basal CPM binding allosterically enhances kB1R affinity for agonist; 2) Kinin substrate (i.e., BK or KD) binding to CPM’s active site causes a conformational change that is transmitted via protein-protein interaction to activate the kB1R without agonist. 3) CPM cleaves the C-terminal Arg of KD (or BK) to generate kB1R agonist that further activates kB1R.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling

Zhang¹,

Brovkovych²,

Zhang³

et al. 2015

Cellular Signalling

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Signaling through the G protein-coupled kinin receptors B1 (kB1R) and B2 (kB2R) plays a critical role in inflammatory responses mediated by activation of the kallikrein-kinin system. The kB2R is constitutively expressed and rapidly desensitized in response to agonist whereas kB1R expression is upregulated by inflammatory stimuli and it is resistant to internalization and desensitization. Here we show that the kB1R heterodimerizes with kB2Rs in co-transfected HEK293 cells and natively expressing endothelial cells, resulting in significant internalization and desensitization of the kB1R response in cells pre-treated with kB2R agonist. However, pre-treatment of cells with kB1R agonist did not affect subsequent kB2R responses. Agonists of other G protein-coupled receptors (thrombin, lysophosphatidic acid) had no effect on a subsequent kB1R response. The loss of kB1R response after pretreatment with kB2R agonist was partially reversed with kB2R mutant Y129S, which blocks kB2R signaling without affecting endocytosis, or T342A, which signals like wild type but is not endocytosed. Co-endocytosis of the kB1R with kB2R was dependent on β-arrestin and clathrin-coated pits but not caveolae. The sorting pathway of kB1R and kB2R after endocytosis differed as recycling of kB1R to the cell surface was much slower than that of kB2R. In cytokine-treated human lung microvascular endothelial cells, pre-treatment with kB2R agonist inhibited kB1R-mediated increase in transendothelial electrical resistance (TER) caused by kB1R stimulation (to generate nitric oxide) and blocked the profound drop in TER caused by kB1R activation in the presence of pyrogallol (a superoxide generator). Thus, kB1R function can be downregulated by kB2R co-endocytosis and signaling, suggesting new approaches to control kB1R signaling in pathological conditions.

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

Cited by 26 publications

References 72 publications

Proteomics of the Human Endometrial Glandular Epithelium and Stroma from the Proliferative and Secretory Phases of the Menstrual Cycle1

Proteomics of the Human Endometrial Glandular Epithelium and Stroma from the Proliferative and Secretory Phases of the Menstrual Cycle1

Kininase 1 As a Preclinical Therapeutic Target for Kinin B1 Receptor in Insulin Resistance

Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling

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