Progress in molecular biology and translational science
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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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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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Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) efficacy, coupled with the phenomenon of orthosteric ligand "bias," offers the prospect of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. As the best-studied non-G protein effectors, arrestins have been shown to mediate a wide range of GPCR signals, and arrestin pathway-selective ligands have been identified for several receptors. ⋯ Yet, when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. While some widely conserved arrestin-regulated biological processes are becoming apparent, what is lacking at present is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will aid drug discovery programs in identifying "biased" ligands with the desired biological effects.
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The discovery that, in addition to mediating G protein-coupled receptor (GPCR) desensitization and endocytosis, arrestins bind to diverse catalytically active nonreceptor proteins and act as ligand-regulated signaling scaffolds led to a paradigm shift in the study of GPCR signal transduction. Research over the past decade has solidified the concept that arrestins confer novel GPCR-signaling capacity by recruiting protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into receptor-based multiprotein "signalsome" complexes. ⋯ While many arrestin-bound kinases and phosphatases are involved in the control of cytoskeletal rearrangement, vesicle endocytosis, exocytosis, and cell migration, other signals reach into the nucleus, affecting cell proliferation, apoptosis, and survival. Indeed, the kinase/phosphatase network regulated by arrestins may be fully as diverse as that regulated by heterotrimeric G proteins.
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Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition. It is classified into several types according to the cerebrovascular amyloid proteins involved [amyloid β-protein (Aβ), cystatin C (ACys), prion protein (APrP), transthyretin (ATTR), gelsolin (AGel), ABri/ADan, and AL]. Sporadic Aβ-type CAA is commonly found in elderly individuals and patients with Alzheimer's disease (AD). ⋯ It has been proposed that cerebrovascular Aβ originates mainly from the brain and is transported to the vascular wall through a perivascular drainage pathway, where it polymerizes into fibrils on vascular basement membrane through interactions with extracellular components. CAA would be promoted by overproduction of Aβ40 (a major molecular species of cerebrovascular Aβ), a decrease of Aβ degradation, or reduction of Aβ clearance due to impairment of perivascular drainage pathway. Further understanding of the molecular pathogenesis of CAA would lead to development of disease-modifying therapies for CAA and CAA-related disorders.