Progress in molecular biology and translational science
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Although all neurons carry the same genetic information, they vary considerably in morphology and functions and respond differently to environmental conditions. Such variability results mostly from differences in gene expression. Among the processes that regulate gene activity, epigenetic mechanisms play a key role and provide an additional layer of complexity to the genome. ⋯ It discusses the role of epigenetic processes in behavioral plasticity triggered by environmental experiences. A particular focus is placed on learning and memory where the importance of epigenetic modifications in brain circuits is best understood. The relevance of epigenetics in memory disorders such as dementia and Alzheimer's disease is also addressed, and promising perspectives for potential epigenetic drug treatment discussed.
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G-protein-coupled receptors mediate responses to external stimuli in various cell types. We are interested in the modulation of KCNQ2/3 potassium channels by the Gq-coupled M1 muscarinic (acetylcholine) receptor (M1R). ⋯ Gq protein-coupled receptors of the plasma membrane activate phospholipase C (PLC) which cleaves the minor plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) into the second messengers diacylgycerol and inositol 1,4,5-trisphosphate, leading to calcium release, protein kinase C (PKC) activation, and PI(4,5)P2 depletion. Combining optical and electrical techniques with knowledge of relative abundance of each signaling component has allowed us to develop a kinetic model and determine that (i) M1R activation and M1R/Gβ interaction are fast; (ii) Gαq/Gβ separation and Gαq/PLC interaction have intermediate time constants; (iii) the amount of activated PLC limits the rate of KCNQ2/3 suppression; (iv) weak PLC activation can elicit robust calcium signals without net PI(4,5)P2 depletion or KCNQ2/3 channel inhibition; and (v) depletion of PI(4,5)P2, and not calcium/CaM or PKC-mediated phosphorylation, closes KCNQ2/3 potassium channels, thereby increasing neuronal excitability.
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Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease leading to respiratory failure. Mutations in telomerase complex genes (TERT or TERC) and short telomeres are genetic risk factors for the development of familial or sporadic idiopathic pulmonary fibrosis. Up to 15% of familial cases and approximately 5% of sporadic cases carry a heterozygous mutation in one of the genes, and patients' cells retain approximately 50% of telomerase activity. ⋯ Short telomeres even in the absence of telomerase mutations are a feature of most patients with idiopathic pulmonary fibrosis. Telomerase mutations also have been linked to pulmonary fibrosis and emphysema syndrome. Although short telomeres have been clearly linked to idiopathic pulmonary fibrosis, the mechanisms of disease are still unclear.