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result sql = A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons.
A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons.
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result sql = Synthesis of glutathione, a major redox regulator, is compromised in schizophrenia. We postulated that the resulting glutathione deficit via its effect on redox-sensitive proteins could contribute to dysfunction of some neurotransmitter systems in schizophrenia. We investigated whether a glutathione deficit, induced by a blocker of glutathione synthesis, L-buthionine-(S,R)-sulfoximine, affects intracellular pathways implicated in dopamine signaling in neurons, namely dopamine modulation of calcium responses to NMDA. Such a glutathione deficit changed the modulation of responses by dopamine, from enhanced responses in control neurons (likely via D1-type receptors) to decreased responses in low-glutathione neurons (via D2-type receptors). THIS DIFFERENCE IN DOPAMINE MODULATION WAS DUE TO A DIFFERENT MODULATION OF L-TYPE CALCIUM CHANNELS ACTIVATED DURING NMDA STIMULATION: dopamine enhanced function of these channels in control neurons but decreased it in low-glutathione neurons. The effect of a glutathione deficit on dopamine signaling was dependent on the redox-sensitive ryanodine receptors (RyRs), whose function was enhanced in low-glutathione neurons. This suggests that enhanced RyRs in low-glutathione neurons strengthens intracellular calcium-dependent pathways following activation of D2-type receptors and causes a decrease in function of L-type channels. This represents a mechanism by which dopaminergic systems could be dysfunctional under conditions of impaired glutathione synthesis as in schizophrenia.

Publication: Free Radic. Biol. Med. 2008 Mar 15 ;44(6)::1042-54. :doi: 10.1016/j.freeradbiomed.2007.12.006.
Publication Date: 2008 Mar 15
Study Author(s): Steullet, Pascal;Lavoie, Suzie;Kraftsik, Rudolf;Guidi, Raffaella;Gysin, René;Cuénod, Michel;Do, Kim Q;
Institution: Center for Psychiatric Neurosciences, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Prilly-Lausanne, Switzerland. [email protected]
Shortcut link to this study:
Synthesis of glutathione, a major redox regulator, is compromised in schizophrenia. We postulated that the resulting glutathione deficit via its effect on redox-sensitive proteins could contribute to dysfunction of some neurotransmitter systems in schizophrenia. We investigated whether a glutathione deficit, induced by a blocker of glutathione synthesis, L-buthionine-(S,R)-sulfoximine, affects intracellular pathways implicated in dopamine signaling in neurons, namely dopamine modulation of calcium responses to NMDA. Such a glutathione deficit changed the modulation of responses by dopamine, from enhanced responses in control neurons (likely via D1-type receptors) to decreased responses in low-glutathione neurons (via D2-type receptors). THIS DIFFERENCE IN DOPAMINE MODULATION WAS DUE TO A DIFFERENT MODULATION OF L-TYPE CALCIUM CHANNELS ACTIVATED DURING NMDA STIMULATION: dopamine enhanced function of these channels in control neurons but decreased it in low-glutathione neurons. The effect of a glutathione deficit on dopamine signaling was dependent on the redox-sensitive ryanodine receptors (RyRs), whose function was enhanced in low-glutathione neurons. This suggests that enhanced RyRs in low-glutathione neurons strengthens intracellular calcium-dependent pathways following activation of D2-type receptors and causes a decrease in function of L-type channels. This represents a mechanism by which dopaminergic systems could be dysfunctional under conditions of impaired glutathione synthesis as in schizophrenia.
PMID: 18206662

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