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1.
Channels (Austin) ; 10(5): 365-378, 2016 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-27253079

RESUMO

ß-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.


Assuntos
Secretases da Proteína Precursora do Amiloide/fisiologia , Ácido Aspártico Endopeptidases/fisiologia , Ativação do Canal Iônico , Doença de Alzheimer/fisiopatologia , Animais , Humanos , Neurônios/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Canais de Sódio Disparados por Voltagem/fisiologia
2.
Mol Neurobiol ; 53(6): 4210-4225, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26215835

RESUMO

The transforming growth factor-ß (TGF-ß) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-ß signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity.


Assuntos
Ativinas/metabolismo , Comportamento Animal , Fenômenos Eletrofisiológicos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Linhagem Celular , Eletrochoque , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteínas Smad/metabolismo , Regulação para Cima
3.
J Mol Cell Cardiol ; 89(Pt B): 335-48, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26454161

RESUMO

KCNQ1 (Kv7.1) proteins form a homotetrameric channel, which produces a voltage-dependent K(+) current. Co-assembly of KCNQ1 with the auxiliary ß-subunit KCNE1 strongly up-regulates this current. In cardiac myocytes, KCNQ1/E1 complexes are thought to give rise to the delayed rectifier current IKs, which contributes to cardiac action potential repolarization. We report here that the type I membrane protein BACE1 (ß-site APP-cleaving enzyme 1), which is best known for its detrimental role in Alzheimer's disease, but is also, as reported here, present in cardiac myocytes, serves as a novel interaction partner of KCNQ1. Using HEK293T cells as heterologous expression system to study the electrophysiological effects of BACE1 and KCNE1 on KCNQ1 in different combinations, our main findings were the following: (1) BACE1 slowed the inactivation of KCNQ1 current producing an increased initial response to depolarizing voltage steps. (2) Activation kinetics of KCNQ1/E1 currents were significantly slowed in the presence of co-expressed BACE1. (3) BACE1 impaired reconstituted cardiac IKs when cardiac action potentials were used as voltage commands, but interestingly augmented the IKs of ATP-deprived cells, suggesting that the effect of BACE1 depends on the metabolic state of the cell. (4) The electrophysiological effects of BACE1 on KCNQ1 reported here were independent of its enzymatic activity, as they were preserved when the proteolytically inactive variant BACE1 D289N was co-transfected in lieu of BACE1 or when BACE1-expressing cells were treated with the BACE1-inhibiting compound C3. (5) Co-immunoprecipitation and fluorescence recovery after photobleaching (FRAP) supported our hypothesis that BACE1 modifies the biophysical properties of IKs by physically interacting with KCNQ1 in a ß-subunit-like fashion. Strongly underscoring the functional significance of this interaction, we detected BACE1 in human iPSC-derived cardiomyocytes and murine cardiac tissue and observed decreased IKs in atrial cardiomyocytes of BACE1-deficient mice.


Assuntos
Secretases da Proteína Precursora do Amiloide/deficiência , Ácido Aspártico Endopeptidases/deficiência , Ativação do Canal Iônico , Canal de Potássio KCNQ1/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Potenciais de Ação , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Feminino , Células HEK293 , Humanos , Imunoprecipitação , Cinética , Masculino , Camundongos , Complexos Multiproteicos/metabolismo , Fenótipo , Ligação Proteica , Proteólise
4.
J Neurosci ; 35(8): 3298-311, 2015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25716831

RESUMO

The ß-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a ß-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.


Assuntos
Potenciais de Ação , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Hipocampo/metabolismo , Canais de Potássio KCNQ/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Células Cultivadas , Feminino , Células HEK293 , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Canais de Potássio KCNQ/genética , Masculino , Camundongos , Ligação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Células Piramidais/metabolismo , Células Piramidais/fisiologia
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