Bradykinin receptor modulation in cellular models of aging and Alzheimer's disease

Jong, Y.-J. I.; Dalemar, L. R.; Seehra, Kuljeet; Baenziger, Nancy Lewis

doi:10.1016/s1567-5769(02)00168-6

Cited by 21 publications

(13 citation statements)

References 32 publications

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“…The regulation of transmitter release, considered to be crucial in the development of the nervous system, was studied in PC12 cells and chromaffin tissue (5)(6)(7)(8). Modulation of the B2BKR is implicated in neurodegeneration occurring during aging and Alzheimer disease (46). The suggestion that dysregulation of B2BKR function and expression could be implicated in the etiology of neurodegeneration and brain diseases is supported by the work of Arganaraz et al (47) who detected an alteration of B2BKR expression in the hippocampus of a rat model of epilepsy.…”

Section: Inhibition Of Formation Of Ebs In the Presence Of The B2bkr mentioning

confidence: 97%

Neuronal Differentiation of P19 Embryonal Carcinoma Cells Modulates Kinin B2 Receptor Gene Expression and Function

Martins

Resende

Majumder

et al. 2005

Journal of Biological Chemistry

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Kinins are vasoactive oligopeptides generated upon proteolytic cleavage of low and high molecular weight kininogens by kallikreins. These peptides have a well established signaling role in inflammation and homeostasis. Nevertheless, emerging evidence suggests that bradykinin and other kinins are stored in the central nervous system and may act as neuromediators in the control of nociceptive response. Here we show that the kinin-B2 receptor (B2BKR) is differentially expressed during in vitro neuronal differentiation of P19 cells. Bradykinin (BK)1 and kallidin are biological active peptides generated by the proteolytic cleavage of kininogens by serine proteases of the kallikrein family. High molecular weight kininogens are precursors of BK, whereas low molecular weight kininogens give origin to kallidin. Along with other kinins, BK and kallidin elicit a wide range of physiological responses, being classically involved in the control of cardiovascular homeostasis and inflammation. As a matter of fact, altered function of the kallikrein-kinin system has been implicated in the development of various pathological conditions such as arthritis, pancreatitis, and asthma (for a review see Refs. 1 and 2). Emerging evidence shows that kinins are stored in neuronal cells of the central nervous system and may act as neuromediators in various functions, including the control of nociceptive information (for a review see Ref.3). Expression of kallikrein in developing rat brains (4) supports the notion that kinin-induced receptor activity might be required during neuronal development. BK has also been shown to enhance the release of neurotransmitters such as noradrenalin and neuropeptide Y by sympathetic neurons, chromaffin cells, and pheochromocytoma cells (5-8). Moreover, BK implication in the control of calcium homeostasis has already been demonstrated in adult sensory neurons (9).Most of the biological actions of BK and kallidin are mediated by a serpentine receptor coupled to a G-protein, the kinin-B2 receptor (B2BKR), which is constitutively expressed and widely distributed throughout central and peripheral tissues under physiological conditions. However, there is evidence that expression of B2BKRs during development is regulated. For instance, B2BKR expression has been shown to be involved in the development of the urinary and cardiovascular systems (10). Inhibition of B2BKR activity in rat embryos resulted in animals with disturbed kidney development (11). Besides being regulated during the ontogenesis of cardiovascular and urinary systems, a large set of evidence exists showing that modulation of B2 receptor expression and function also appears during neuronal development. Thus, it has been detected in central and peripheral noradrenergic neurons, in the spinal cord, in neuronal differentiating PC12 pheochromocytoma cells, and in neuroblastoma and glia-derived cell lines (12-18). A cross-talk between the B2BKR and other hormone and neurotransmitter

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Section: Inhibition Of Formation Of Ebs In the Presence Of The B2bkr mentioning

confidence: 97%

Neuronal Differentiation of P19 Embryonal Carcinoma Cells Modulates Kinin B2 Receptor Gene Expression and Function

Martins

Resende

Majumder

et al. 2005

Journal of Biological Chemistry

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“…Furthermore, a pharmacodynamic modulation of BK receptors and an increase in the phosphorylation of various proteins were observed in a cellular model of AD, after stimulation with BK (Jong et al, 2002;Zhao et al, 2002).…”

Section: Introductionmentioning

confidence: 95%

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

Caetano¹,

Dong-Creste²,

Amaral³

et al. 2015

Neuropeptides

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“…A common element of this molecular profile appearing in all presenilin and non-presenilin-based genetic forms of AD risk we tested is the initial BK-induced BKB2R Tyr phosphorylation itself, positioned early in the BKB2R signaling cascade [8], [12], [13], [14]. Beyond this initial step, our present studies now reveal multiple points of divergence in the downstream signaling cascades in AD cells of differing genetic origins.…”

Section: Discussionmentioning

confidence: 55%

“…The altered PKC-dependent signal transduction pathway we defined in skin fibroblasts from AD patients, yielding BKB2R modulated by phosphorylation [8], [13], [14], is discernible in Trisomy 21 fibroblasts decades before the characteristic age of onset of symptomatic AD. A common element of this molecular profile appearing in all presenilin and non-presenilin-based genetic forms of AD risk we tested is the initial BK-induced BKB2R Tyr phosphorylation itself, positioned early in the BKB2R signaling cascade [8], [12], [13], [14].…”

Section: Discussionmentioning

confidence: 96%

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Molecular Profiling Reveals Diversity of Stress Signal Transduction Cascades in Highly Penetrant Alzheimer's Disease Human Skin Fibroblasts

et al. 2009

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The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD) as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R) inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival pathway in normal fibroblasts lost in PS-1 M146L fibroblasts. Complex molecular profiles of signaling dysfunction in the most putatively straightforward human cellular models of AD suggest that risk ascertainment and therapeutic interventions in AD as a whole will likely demand complex solutions.

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Bradykinin receptor modulation in cellular models of aging and Alzheimer's disease

Cited by 21 publications

References 32 publications

Neuronal Differentiation of P19 Embryonal Carcinoma Cells Modulates Kinin B2 Receptor Gene Expression and Function

Neuronal Differentiation of P19 Embryonal Carcinoma Cells Modulates Kinin B2 Receptor Gene Expression and Function

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

Molecular Profiling Reveals Diversity of Stress Signal Transduction Cascades in Highly Penetrant Alzheimer's Disease Human Skin Fibroblasts

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