Behavioral Pharmacology of Gap Junctions
01 Jan 2013-pp 261-276
TL;DR: G gap junction blockers may induce various side-effects related to emotions, mood, locomotor activity and coordination in predisposed subjects and their role in regulation of the sleep–wake cycle, memory, learning and attention is implicated.
Abstract: The gap junction blockers most often used in behavioral experiments are carbenoxolone, quinine, quinidine and mefloquine. Importantly, these four drugs are used also in medicine and, therefore, it is possible to compare the results obtained in animal studies with subjective experiences reported by humans. Available data suggest that gap junction blockers may exert both inhibitory and excitatory effects and the net effect depends on the current state of the brain and individual predisposition. Therefore, gap junction blockers may induce various side-effects related to emotions, mood, locomotor activity and coordination in predisposed subjects. Available experimental evidence also implicates gap junctions in regulation of the sleep–wake cycle, memory, learning and attention, and in the mechanism of tremor, epilepsy and inflammation-induced pain sensitization.
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TL;DR: A review of microarray reports revealed 88 genes whose transcription is consistently regulated by glucocorticoids (GCs), such as cortisol, corticosterone and dexamethasone, in the brain this article.
Abstract: The identification of key genes in transcriptomic data constitutes a huge challenge. Our review of microarray reports revealed 88 genes whose transcription is consistently regulated by glucocorticoids (GCs), such as cortisol, corticosterone and dexamethasone, in the brain. Replicable transcriptomic data were combined with biochemical and physiological data to create an integrated view of the effects induced by GCs. The most frequently reported genes were Errfi1 and Ddit4. Their up-regulation was associated with the altered transcription of genes regulating growth factor and mTORC1 signaling (Gab1, Tsc22d3, Dusp1, Ndrg2, Ppp5c and Sesn1) and progression of the cell cycle (Ccnd1, Cdkn1a and Cables1). The GC-induced reprogramming of cell function involves changes in the mRNA level of genes responsible for the regulation of transcription (Klf9, Bcl6, Klf15, Tle3, Cxxc5, Litaf, Tle4, Jun, Sox4, Sox2, Sox9, Irf1, Sall2, Nfkbia and Id1) and the selective degradation of mRNA (Tob2). Other genes are involved in the regulation of metabolism (Gpd1, Aldoc and Pdk4), actin cytoskeleton (Myh2, Nedd9, Mical2, Rhou, Arl4d, Osbpl3, Arhgef3, Sdc4, Rdx, Wipf3, Chst1 and Hepacam), autophagy (Eva1a and Plekhf1), vesicular transport (Rhob, Ehd3, Vps37b and Scamp2), gap junctions (Gjb6), immune response (Tiparp, Mertk, Lyve1 and Il6r), signaling mediated by thyroid hormones (Thra and Sult1a1), calcium (Calm2), adrenaline/noradrenaline (Adcy9 and Adra1d), neuropeptide Y (Npy1r) and histamine (Hdc). GCs also affected genes involved in the synthesis of polyamines (Azin1) and taurine (Cdo1). The actions of GCs are restrained by feedback mechanisms depending on the transcription of Sgk1, Fkbp5 and Nr3c1. A side effect induced by GCs is increased production of reactive oxygen species. Available data show that the brain's response to GCs is part of an emergency mode characterized by inactivation of non-core activities, restrained inflammation, restriction of investments (growth), improved efficiency of energy production and the removal of unnecessary or malfunctioning cellular components to conserve energy and maintain nutrient supply during the stress response.
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Cites background from "Behavioral Pharmacology of Gap Junc..."
...Although there are several types of connexins (Juszczak and Swiergiel, 2009; Juszczak and Swiergiel, 2013), microarray studies revealed consistent changes in the transcription of only Gjb6 (Gap junction protein, beta 6) (Carter et al., 2012; Datson et al., 2011, 2013; Peffer et al., 2014)....
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...Although there are several types of connexins (Juszczak and Swiergiel, 2009; Juszczak and Swiergiel, 2013), microarray studies revealed consistent changes in the transcription of only Gjb6 (Gap junction protein, beta 6) (Carter et al....
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...…transmission of dilating signals from neurons to arterioles, the trafficking of glucose from blood vessels to neurons, the clearance of extracellular glutamate released from synapses and the maintenance of ion homeostasis, which is crucial for neuronal excitability (Juszczak and Swiergiel, 2013)....
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...Astrocytic gap junctions are important for brain function because they enable the exchange of small molecules between cells and therefore participate in the transmission of dilating signals from neurons to arterioles, the trafficking of glucose from blood vessels to neurons, the clearance of extracellular glutamate released from synapses and the maintenance of ion homeostasis, which is crucial for neuronal excitability (Juszczak and Swiergiel, 2013)....
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References
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1,107 citations
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966 citations
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825 citations
TL;DR: It is shown that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks for the delivery of energetic metabolites from blood vessels to distal neurons.
Abstract: Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.
739 citations