scholarly journals Calcium/Calmodulin–Dependent Protein Kinase II in Cerebrovascular Diseases

2021 ◽  
Author(s):  
Xuejing Zhang ◽  
Jaclyn Connelly ◽  
Edwin S. Levitan ◽  
Dandan Sun ◽  
Jane Q. Wang
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cerebrovascular Diseases ◽  
Biological Processes ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
The Brain

AbstractCerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca2+ sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing understanding of the importance of neurovascular interactions in cerebrovascular diseases, there are clearly gaps in our understanding of how CaMKII functions in the complex neurovascular biological processes and its contributions to cerebrovascular diseases. Additionally, emerging evidence demonstrates novel regulatory mechanisms of CaMKII and potential roles of the less-studied CaMKII isoforms in the ischemic brain, which has sparked renewed interests in this dynamic kinase family. This review discusses past findings and emerging evidence on CaMKII in several major cerebrovascular dysfunctions including ischemic stroke, hemorrhagic stroke, and vascular dementia, focusing on the unique roles played by CaMKII in the underlying biological processes of neuronal cell death, neuroinflammation, and endothelial barrier dysfunction triggered by stroke. We also highlight exciting new findings, promising therapeutic agents, and future perspectives for CaMKII in cerebrovascular systems.

scholarly journals Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

2019 ◽  
Vol 20 (13) ◽  
pp. 3131 ◽  
Author(s):  
Nami Kim ◽  
Dongmei Chen ◽  
Xiao Zhen Zhou ◽  
Tae Ho Lee
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Biological Processes ◽  
Death Associated Protein Kinase ◽  
The Brain

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.

scholarly journals Activation State-Dependent Substrate Gating in Ca2+/Calmodulin-Dependent Protein Kinase II

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
D. E. Johnson ◽  
A. Hudmon
Keyword(s):  
Protein Kinase ◽  
Catalytic Domain ◽  
Intrinsic Property ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
State Dependent ◽  
Protein Kinase Ii ◽  
Dependent Protein ◽  
Substrate Phosphorylation ◽  
The Brain

Calcium/calmodulin-dependent protein kinase II (CaMKII) is highly concentrated in the brain where its activation by the Ca2+sensor CaM, multivalent structure, and complex autoregulatory features make it an ideal translator of Ca2+signals created by different patterns of neuronal activity. We provide direct evidence that graded levels of kinase activity and extent of T287(T286αisoform) autophosphorylation drive changes in catalytic output and substrate selectivity. The catalytic domains of CaMKII phosphorylate purified PSDs much more effectively when tethered together in the holoenzyme versus individual subunits. Using multisubstrate SPOT arrays, high-affinity substrates are preferentially phosphorylated with limited subunit activity per holoenzyme, whereas multiple subunits or maximal subunit activation is required for intermediate- and low-affinity, weak substrates, respectively. Using a monomeric form of CaMKII to control T287autophosphorylation, we demonstrate that increased Ca2+/CaM-dependent activity for all substrates tested, with the extent of weak, low-affinity substrate phosphorylation governed by the extent of T287autophosphorylation. Our data suggest T287autophosphorylation regulates substrate gating, an intrinsic property of the catalytic domain, which is amplified within the multivalent architecture of the CaMKII holoenzyme.

scholarly journals Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1702
Author(s):  
Sereen Sandouka ◽  
Tawfeeq Shekh-Ahmad
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Antioxidant Capacity ◽  
Temporal Lobe ◽  
Epileptiform Activity ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

scholarly journals miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke

2016 ◽  
Vol Volume 12 ◽  
pp. 3083-3092 ◽  
Author(s):  
Shengtao Yao ◽  
Bo Tang ◽  
Gang Li ◽  
Ruiming Fan ◽  
Fang Cao
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

scholarly journals CaMKIIβ in Neuronal Development and Plasticity: An Emerging Candidate in Brain Diseases

2020 ◽  
Vol 21 (19) ◽  
pp. 7272
Author(s):  
Olivier Nicole ◽  
Emilie Pacary
Keyword(s):  
Neuronal Plasticity ◽  
Neuronal Development ◽  
Brain Diseases ◽  
Dependent Protein Kinase ◽  
Potential Implication ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
The Subject ◽  
The Brain ◽  
Intense Research

The calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous and central player in Ca2+ signaling that is best known for its functions in the brain. In particular, the α isoform of CaMKII has been the subject of intense research and it has been established as a central regulator of neuronal plasticity. In contrast, little attention has been paid to CaMKIIβ, the other predominant brain isoform that interacts directly with the actin cytoskeleton, and the functions of CaMKIIβ in this organ remain largely unexplored. However, recently, the perturbation of CaMKIIβ expression has been associated with multiple neuropsychiatric and neurodevelopmental diseases, highlighting CAMK2B as a gene of interest. Herein, after highlighting the main structural and expression differences between the α and β isoforms, we will review the specific functions of CaMKIIβ, as described so far, in neuronal development and plasticity, as well as its potential implication in brain diseases.

Abstract W P210: Plasma Kallikrein Induces Ischemic Brain Damage Through Cleavage-Dependent Activation of NMDA Receptors

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Gongxiong wu ◽  
Long-Jun Wu ◽  
David E. Clapham ◽  
Edward P. Feener
Keyword(s):  
Cell Culture ◽  
Cell Death ◽  
Ischemic Stroke ◽  
Nmda Receptor ◽  
Brain Damage ◽  
Infarct Volume ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Plasma Kallikrein ◽  
Ischemic Brain

Background and Purpose: Ischemic stroke ultimately leads to brain dysfunction and neurological deficits. However, the mechanisms that contribute to neuronal injury and dysfunction in ischemic stroke are not fully understood. Recent studies have shown that pharmacological inhibition of the serine protease plasma kallikrein (PK) reduced neuron death and neurological impairment in ischemic brain in mice. In this study, we examine the effects of PK on the neuronal cell death and brain damage in mice and investigate the molecular mechanism of PK-induced neuronal cell death in ischemic stroke. Methods: Ischemia was produced in wild-type (WT) and PK knockout mice by permanent middle cerebral artery occlusion (pMCAO). Infarct volume was quantified by TTC staining and brain function was evaluated by neurological scoring. The effect of PK on neuron cell death in cell culture was determined by lactate dehydrogenase (LDH) release. NMDA receptor function was measured by patch clamp and Ca2+ imaging. NR1 cleavage was detected by western blot. The effect of systemic PK inhibition on pMCAO-induced infarct volume was evaluated in mice treated with the PK inhibitor (BPCCB) or vehicle alone delivered using subcutaneously implanted osmotic pumps. Results: We show that PK deficiency in mice decreased MCAO-induced infarct volume by 39.8% (P<0.01) and improved neurological function compared responses in WT mice. Addition of PK to cell culture media enhanced NMDA-induced cell death of cortical neurons. We further show that PK induced cleavage of NR1 and identify the cleavage site in the extracellular N-terminal domain of NR1. The truncated form of NR1 displayed enhanced NMDA-stimulated current and calcium influx. Treatment of mice with a PK inhibitor reduced MCAO-induced brain damage and neuronal injury. Conclusions: PK enhances NMDA receptor-mediated excitotoxicity and ischemic neuronal death. These findings suggest that PK may serve as a potential therapeutic target for treatment of ischemic stroke.

Abstract P801: Impact of Oxidized Phospholipids on Outcomes From Cerebral Ischemia and Reperfusion Injury

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Jin Yu ◽  
Hong Zhu ◽  
Calvin Yeang ◽  
Joseph L Witztum ◽  
Sotirios Tsimikas ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemia And Reperfusion ◽  
Oxidized Phospholipids ◽  
Ischemia And Reperfusion Injury ◽  
Cerebral Ischemia And Reperfusion ◽  
The Brain

The mechanisms leading to oxidative stress and cellular dysfunction during stroke are not well understood. To test the hypothesis that transient cerebral artery occlusion (MCAo) in mice results in the generation of oxidized phospholipids (oxPLs) that contribute to neuronal cell death and glial activation. Both in vitro and in vivo cerebral ischemia and reperfusion injury (IRI) resulted in the elevation of specific oxPLs. Neuronal cell death was determined in the presence of oxPLs and the natural oxPL E06 antibody protected the cells from the toxic effects. IRI in mice gave rise to increased immunoreactivity of oxPLs in the brain. E06 reduced inflammatory markers in the brain following IRI, including iba-1, GFAP and inflammatory cytokines. In addition, oxPLs gave rise to M1 and Mox microglial phenotypes which was reversed in the presence of E06 and elicited a more M2 phenotype. Nrf2 deficient mice show increased infarct volumes and microglia from Nrf2 -/- mice show a reduction in Mox gene expression, and E06 protects both mice and cells from the Nrf2 deficit. Cerebral IRI generates oxPLs which triggers neuronal cell loss and inflammation and inactivation of oxPLs in vivo reduces infarct volume and improves outcomes.

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