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Role of intracellular calcium on ethanol-induced activation of protein kinase A: molecular model and behavioral consequences

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Role of intracellular calcium on ethanol-induced activation of protein kinase A: molecular model and behavioral consequences

dc.contributor.advisor	González Aragón, Carlos Manuel
dc.contributor.advisor	Nácher Roselló, Juan Salvador
dc.contributor.author	Baliño Remiro, Pablo
dc.contributor.other	Departament de Biologia Cel.lular i Parasitologia	es_ES
dc.date.accessioned	2014-02-17T11:21:41Z
dc.date.available	2014-05-19T06:10:03Z
dc.date.issued	2014
dc.date.submitted	26-02-2014	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/32973
dc.description.abstract	Ethanol can be considered a weak drug when compared to most other drugs of abuse. The molecule of ethanol has no asymmetric carbon. Being so, it does not interact with the biological substrates in a stereoselective way as most of the receptor ligand drugs do. Moreover, ethanol has a very simple chemical structure. Thus, the hydroxyl group provides a dipole that allows the formation of hydrogen bonds. It is the formation of hydrogen bonds that makes ethanol soluble in water. In contrast, ethanol presents an aliphatic moiety that provides a lipophilic group that can interact with non-polar cellular elements. However, contrary to what it is generally believed, ethanol has low lipid solubility. All these chemical properties of ethanol have led different authors to consider the first oxidative metabolite of ethanol as the biologically active compound. Nonetheless, ethanol produces quite complex effects on neuronal systems. Behavioral changes observed after ethanol administration are produced within very short periods of time (< 5 min). In this respect mobilization and/or modulation of some of these described ethanol neuronal substrates, requires reorganization of protein structures and/or in some cases early gene expression. It is unlikely that ethanol actions after acute administered are explained by processes such as induction of gene expression or new protein synthesis. As such, primary ethanol interactions among the neuronal substrate must be mediated by cellular mechanisms that can be controlled and triggered almost immediately. Interestingly, one of these posttranscriptional mechanisms that lead to protein modification is the phosphorylation, carried out by the activity of protein kinases. They represent one of the major classes of cell-regulatory molecules and are important mediators in signal-transduction pathways that affect cell physiology and behavior. In this respect, most of the previously described ethanol molecular targets require posttranscriptional phosphorylation to be fully active (DARPP-32, Fyn, etc). One key protein kinase that has been described as an important mediator involved in the neurobehavioral responses to ethanol is the cAMP dependent protein kinase (PKA). This kinase is the end point of a cAMP-dependent intracellular pathway. Moreover, this cAMP-dependent cascade is conformed by different intermediates that are Ca2+ sensitive (Hanoune and Defer, 2001, Nelson et al., 2003; Cali et al., 1994; Wang et al., 2003, Maas et al., 2005). All together, this pathway is conformed by different elements that control and modulate the activity of the PKA. The activated PKA transmits information rapidly across the cell and promotes changes in the cellular machinery and also is involved in the modulation of several ethanol neurobehavioral effects. Manipulations of the cAMP-dependent cascade modulate the acute stimulant effects of ethanol, ethanol-induced behavioral sensitization (Freund and Palmer, 1997; Tolliver et al., 1999; Hayes et al., 2012), ethanol sensitivity (Thiele et al., 2000; Wand et al., 2001), and ethanol intake (Pandey et al., 2005). Given this, in the present work we aimed to study the role of cellular Ca2+ distribution and flux on the modulation of a PKA/cAMP-dependent cascade as an ethanol central mechanism of action.	es_ES
dc.format.extent	223 p.	es_ES
dc.language.iso	en_US	es_ES
dc.subject	mice	es_ES
dc.subject	calcium	es_ES
dc.subject	protein kinase A	es_ES
dc.subject	ethanol mechanism of action	es_ES
dc.title	Role of intracellular calcium on ethanol-induced activation of protein kinase A: molecular model and behavioral consequences	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::CIENCIAS DE LA VIDA::Neurociencias	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS ::Farmacología	es_ES
dc.embargo.terms	3 months	es_ES