scholarly journals Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor

2010 ◽  
Vol 298 (6) ◽  
pp. H1652-H1660 ◽  
Author(s):  
Christina U. Lorentz ◽  
Eric N. Alston ◽  
Todd Belcik ◽  
Jonathan R. Lindner ◽  
George D. Giraud ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Sympathetic Nerves ◽  
Nerve Fibers ◽  
Receptor Expression ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Semaphorin 3A

Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR−/−) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR−/− ventricles and discovered that the subendocardium of the p75NTR−/− left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/d t, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons

2005 ◽  
Vol 65 (2) ◽  
pp. 192-204 ◽  
Author(s):  
Wohaib Hasan ◽  
H. Jesse Smith ◽  
Alison Y. Ting ◽  
Peter G. Smith
Keyword(s):  
Sympathetic Neurons ◽  
Receptor Expression ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

2014 ◽  
Vol 112 (11) ◽  
pp. 951-959 ◽  
Author(s):  
Morten Eriksen ◽  
Arnfinn Ilebekk ◽  
Alessandro Cataliotti ◽  
Cathrine Rein Carlson ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker

SummaryBradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

scholarly journals Isoflurane Neurotoxicity Is Mediated by p75NTR-RhoA Activation and Actin Depolymerization

2011 ◽  
Vol 114 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Brian P. Lemkuil ◽  
Brian P. Head ◽  
Matthew L. Pearn ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Actin Depolymerization ◽  
Rhoa Activation ◽  
Hippocampal Slice Cultures ◽  
Developing Neurons

Background The mechanisms by which isoflurane injured the developing brain are not clear. Recent work has demonstrated that it is mediated in part by activation of p75 neurotrophin receptor. This receptor activates RhoA, a small guanosine triphosphatase that can depolymerize actin. It is therefore conceivable that inhibition of RhoA or prevention of cytoskeletal depolymerization might attenuate isoflurane neurotoxicity. This study was conducted to test these hypotheses using primary cultured neurons and hippocampal slice cultures from neonatal mouse pups. Methods Primary neuron cultures (days in vitro, 4-7) and hippocampal slice cultures from postnatal day 4-7 mice were exposed to 1.4% isoflurane (4 h). Neurons were pretreated with TAT-Pep5, an intracellular inhibitor of p75 neurotrophin receptor, the cytoskeletal stabilizer jasplakinolide, or their corresponding vehicles. Hippocampal slice cultures were pretreated with TAT-Pep5 before isoflurane exposure. RhoA activation was evaluated by immunoblot. Cytoskeletal depolymerization and apoptosis were evaluated with immunofluorescence microscopy using drebrin and cleaved caspase-3 staining, respectively. Results RhoA activation was increased after 30 and 120 min of isoflurane exposure in neurons; TAT-Pep5 (10 μm) decreased isoflurane-mediated RhoA activation at both time intervals. Isoflurane decreased drebrin immunofluorescence and enhanced cleaved caspase-3 in neurons, effects that were attenuated by pretreatment with either jasplakinolide (1 μm) or TAT-Pep5. TAT-Pep5 attenuated the isoflurane-mediated decrease in phalloidin immunofluorescence. TAT-Pep5 significantly attenuated isoflurane-mediated loss of drebrin immunofluorescence in hippocampal slices. Conclusions Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis. Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity in developing neurons.

scholarly journals proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bangkun Yang ◽  
Lesheng Wang ◽  
Ying Nie ◽  
Wei Wei ◽  
Wenping Xiong
Keyword(s):  
Neural Plasticity ◽  
Cell Model ◽  
Neurotrophin Receptor ◽  
Control Group ◽  
P75 Neurotrophin Receptor ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
Cellular Apoptosis ◽  
Related Proteins

AbstractBrain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

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