RESUMO
Considering that calcium/calmodulin-dependent kinase 4 (CAMK4) plays a pivotal role in blood pressure regulation, we investigated the association between a CAMK4 polymorphism (rs10491334) and hypertension in the Han, Kazak, and Uygur ethnic groups. We studied 1224 patients with hypertension and 967 normotensive controls classified into three ethnic groups (Han, Kazak, and Uygur). The rs10491334 polymorphism was genotyped using a TaqMan® 5'-nuclease assay. In the Uygur group, the T-allele frequency in patients with hypertension was twice that of the controls (12.5 vs 6.38%), and T-allele carriers had a significantly increased risk of hypertension compared with non-carriers (odds ratio = 2.200; 95% confidence interval = 1.473-3.285, P < 0.001). However, no significant correlation was found in the Han and Kazak groups. The T-allele of rs10491334 in CAMK4 was associated with hypertension in the Uygur group.
Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Predisposição Genética para Doença , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Povo Asiático , Estudos de Casos e Controles , Etnicidade , Feminino , Expressão Gênica , Frequência do Gene , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of beta-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide.
Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Transdução de Sinais/fisiologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Biologia Computacional , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Cloreto de Lítio/farmacologia , Cloreto de Lítio/uso terapêutico , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Testes Neuropsicológicos , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Ratos , Ratos Endogâmicos , Fatores de Transcrição TCF/metabolismo , Transfecção , Proteínas Wnt/farmacologia , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/genéticaRESUMO
The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.