Assuntos
Cromatina , Linfoma , Cromatina/genética , Histonas/genética , Histonas/metabolismo , Humanos , MetilaçãoAssuntos
Glicemia/metabolismo , Derivação Gástrica , Glucose/metabolismo , Jejuno/metabolismo , Animais , MasculinoRESUMO
Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.
Assuntos
Dopamina/fisiologia , Neurônios Dopaminérgicos/enzimologia , Mesencéfalo/fisiologia , Oxigenases de Função Mista/fisiologia , Oxo-Ácido-Liases/fisiologia , Adenina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Cocaína/farmacologia , Corpo Estriado/fisiologia , Neurônios Dopaminérgicos/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Metilação , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigenases de Função Mista/deficiência , Oxigenases de Função Mista/genética , Oxo-Ácido-Liases/deficiência , Oxo-Ácido-Liases/genética , Fenótipo , Quimpirol/farmacologia , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/deficiência , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3/fisiologia , Recompensa , Transdução de Sinais/efeitos dos fármacosRESUMO
Insulin-like growth factor (IGF-I) signaling has been implicated to play an important role in regulation of cardiac growth, hypertrophy, and contractile function and has been linked to the development of age-related congestive heart failure. Here, we address the question to what extent cardiomyocyte-specific IGF-I signaling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF-I signaling in the adult heart without confounding effects due to IGF-I overexpression or adaptation during embryonic and early postnatal development, we inactivated the IGF-I receptor (IGF-IR) by a 4-hydroxytamoxifen-inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF-IR (iCMIGF-IRKO) as assessed by Western analysis and real-time PCR went along with reduced IGF-I-dependent Akt and GSK3ß phosphorylation. Functional analysis by conductance manometry and MRI revealed no functional alterations in young adult iCMIGF-IRKO mice (age 3 mo). However, when induced in aging mice (11 mo) diastolic cardiac function was depressed. To address the question whether insulin signaling might compensate for the defective IGF-IR signaling, we inactivated ß-cells by streptozotocin. However, the diabetes-associated functional depression was similar in control and iCMIGF-IRKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF-IR signaling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts.