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1.
Anesth Analg ; 129(6): 1529-1535, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31743172

RESUMO

BACKGROUND: Dexmedetomidine (Dex) is an attractive agent for procedural sedation due to its unique pharmacodynamic profile, specifically affording predictable sedation without concurrent respiratory depression. However, Dex has previously been reported to prevent or terminate arrhythmias. The purpose of this study was to investigate paroxysmal supraventricular tachycardia (PSVT) inducibility and homeostatic stability during electrophysiology studies (EPSs) and ablation when a standardized Dex protocol was used as the primary sedation agent. METHODS: We performed a retrospective review of 163 consecutive procedures for PSVT ablation that received Dex as the primary sedative with adjunct fentanyl and midazolam boluses (DEX-FENT-MIDAZ). This cohort was compared to 163 consecutive control procedures wherein strictly fentanyl and midazolam were used for sedation. The primary outcome reviewed was PSVT inducibility assessed before ablation. Reviewed secondary outcomes included level of sedation and intraprocedure hemodynamics and oxygenation. RESULTS: The arrhythmia profiles of the DEX-FENT-MIDAZ and control cohorts were very similar. The overall incidence of a "negative" EPSs in which arrhythmia was not induced was 24% in the DEX-FENT-MIDAZ group and 26% in the control group (P = .7). Unintended deep sedation was significantly less with DEX-FENT-MIDAZ (4.3% vs 27%; P ≤ .0001). However, DEX-FENT-MIDAZ use was associated with a higher incidence of intraprocedure hypotension. CONCLUSIONS: Dex sedation during EPSs is not associated with a reduction in PSVT inducibility. The therapeutic utility of Dex during EPS arises from the predictable sedation Dex affords but is associated with an increased incidence of intraprocedure hypotension.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Ablação por Cateter , Dexmedetomidina/uso terapêutico , Técnicas Eletrofisiológicas Cardíacas , Frequência Cardíaca , Hipnóticos e Sedativos/uso terapêutico , Taquicardia Supraventricular/cirurgia , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Estimulação Cardíaca Artificial , Dexmedetomidina/efeitos adversos , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipotensão/induzido quimicamente , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/fisiopatologia , Resultado do Tratamento
2.
J Biol Chem ; 288(17): 12353-65, 2013 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-23486469

RESUMO

Fission and fusion events dynamically control the shape and function of mitochondria. The activity of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is finely tuned by several post-translational modifications. Phosphorylation of Ser-656 by cAMP-dependent protein kinase (PKA) inhibits Drp1, whereas dephosphorylation by a mitochondrial protein phosphatase 2A isoform and the calcium-calmodulin-dependent phosphatase calcineurin (CaN) activates Drp1. Here, we identify a conserved CaN docking site on Drp1, an LXVP motif, which mediates the interaction between the phosphatase and mechanoenzyme. We mutated the LXVP motif in Drp1 to either increase or decrease similarity to the prototypical LXVP motif in the transcription factor NFAT, and assessed stability of the mutant Drp1-CaN complexes by affinity precipitation and isothermal titration calorimetry. Furthermore, we quantified effects of LXVP mutations on Drp1 dephosphorylation kinetics in vitro and in intact cells. With tools for bidirectional control of the CaN-Drp1 signaling axis in hand, we demonstrate that the Drp1 LXVP motif shapes mitochondria in neuronal and non-neuronal cells, and that CaN-mediated Drp1 dephosphorylation promotes neuronal death following oxygen-glucose deprivation. These results point to the CaN-Drp1 complex as a potential target for neuroprotective therapy of ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Dinaminas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Acidente Vascular Cerebral/metabolismo , Motivos de Aminoácidos , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Calcineurina/genética , Calcineurina/metabolismo , Morte Celular , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinaminas/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Fosforilação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
3.
Neurobiol Dis ; 51: 13-26, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22297163

RESUMO

Nascent evidence indicates that mitochondrial fission, fusion, and transport are subject to intricate regulatory mechanisms that intersect with both well-characterized and emerging signaling pathways. While it is well established that mutations in components of the mitochondrial fission/fusion machinery can cause neurological disorders, relatively little is known about upstream regulators of mitochondrial dynamics and their role in neurodegeneration. Here, we review posttranslational regulation of mitochondrial fission/fusion enzymes, with particular emphasis on dynamin-related protein 1 (Drp1), as well as outer mitochondrial signaling complexes involving protein kinases and phosphatases. We also review recent evidence that mitochondrial dynamics has profound consequences for neuronal development and synaptic transmission and discuss implications for clinical translation.


Assuntos
Dinâmica Mitocondrial/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/patologia
4.
PLoS One ; 16(1): e0238799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33434191

RESUMO

Exposure to volatile anesthetics during the neonatal period results in acute neuron death. Prior work suggests that apoptosis is the dominant mechanism mediating neuron death. We show that Bax deficiency blocks neuronal death following exposure to isoflurane during the neonatal period. Blocking Bax-mediated neuron death attenuated the neuroinflammatory response of microglia following isoflurane exposure. We find that GABAergic interneurons are disproportionately overrepresented among dying neurons. Despite the increase in neuronal apoptosis induced by isoflurane exposure during the neonatal period, seizure susceptibility, spatial memory retention, and contextual fear memory were unaffected later in life. However, Bax deficiency alone led to mild deficiencies in spatial memory and contextual fear memory, suggesting that normal developmental apoptotic death is important for cognitive function. Collectively, these findings show that while GABAergic neurons in the neonatal brain undergo elevated Bax-dependent apoptotic cell death following exposure to isoflurane, this does not appear to have long-lasting consequences on overall neurological function later in life.


Assuntos
Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Isoflurano/efeitos adversos , Anestésicos Inalatórios/farmacologia , Animais , Animais Recém-Nascidos/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Interneurônios/metabolismo , Isoflurano/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Microglia/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/fisiologia
5.
J Cereb Blood Flow Metab ; 38(12): 2192-2208, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30009645

RESUMO

Administration of anesthetic agents fundamentally shifts the responsibility for maintenance of homeostasis from the patient and their intrinsic physiological regulatory mechanisms to the anesthesiologist. Continuous delivery of oxygen and nutrients to the brain is necessary to prevent irreversible injury and arises from a complex series of regulatory mechanisms that ensure uninterrupted cerebral blood flow. Our understanding of these regulatory mechanisms and the effects of anesthetics on them has been driven by the tireless work of pioneers in the field. It is of paramount importance that the anesthesiologist shares this understanding. Herein, we will review the physiological determinants of cerebral blood flow and how delivery of anesthesia impacts these processes.


Assuntos
Anestésicos/farmacologia , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Anestesia/efeitos adversos , Anestesia/métodos , Animais , Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Humanos
6.
FEBS J ; 280(2): 662-73, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22583914

RESUMO

The neuron-specific Bß2 regulatory subunit of protein phosphatase 2A (PP2A), a product of the spinocerebellar ataxia type 12 disease gene PPP2R2B, recruits heterotrimeric PP2A to the outer mitochondrial membrane (OMM) through its N-terminal mitochondrial targeting sequence. OMM-localized PP2A/Bß2 induces mitochondrial fragmentation, thereby increasing susceptibility to neuronal insults. Here, we report that PP2A/Bß2 activates the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) by dephosphorylating Ser656, a highly conserved inhibitory phosphorylation site targeted by the neuroprotective protein kinase A-A kinase anchoring protein 1 complex. We further show that translocation of PP2A/Bß2 to mitochondria is regulated by phosphorylation of Bß2 at three N-terminal serines. Phosphomimetic substitution of Ser20, Ser21, and Ser22 renders Bß2 cytosolic, blocks Drp1 dephosphorylation and mitochondrial fragmentation, and abolishes the ability of Bß2 overexpression to induce apoptosis in cultured hippocampal neurons. Alanine substitution of Ser20-Ser22 to prevent phosphorylation has the opposite effect, promoting association of Bß2 with mitochondria, Drp1 dephosphorylation, mitochondrial fission, and neuronal death. OMM translocation of Bß2 can be attenuated by mutation of residues in close proximity to the catalytic site, but only if Ser20-Ser22 are available for phosphorylation, suggesting that PP2A/Bß2 autodephosphorylation is necessary for OMM association, probably by uncovering the net positive charge of the mitochondrial targeting sequence. These results reveal another layer of complexity in the regulation of the mitochondrial fission-fusion equilibrium and its physiological and pathophysiological consequences in the nervous system.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Fosfatase 2/metabolismo , Alanina/genética , Alanina/metabolismo , Substituição de Aminoácidos , Animais , Apoptose/genética , Células COS , Sobrevivência Celular/genética , Células Cultivadas , Dinaminas , GTP Fosfo-Hidrolases/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Células HeLa , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Immunoblotting , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/metabolismo , Fosforilação , Proteína Fosfatase 2/genética , Transporte Proteico , Serina/genética , Serina/metabolismo
7.
Enzyme Res ; 2011: 398751, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21755039

RESUMO

Protein phosphatase 2A- (PP2A-) catalyzed dephosphorylation of target substrate proteins is widespread and critical for cellular function. PP2A is predominantly found as a heterotrimeric complex of a catalytic subunit (C), a scaffolding subunit (A), and one member of 4 families of regulatory subunits (B). Substrate specificity of the holoenzyme complex is determined by the subcellular locale the complex is confined to, selective incorporation of the B subunit, interactions with endogenous inhibitory proteins, and specific intermolecular interactions between PP2A and target substrates. Here, we discuss recent studies that have advanced our understanding of the molecular determinants for PP2A substrate specificity.

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