A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons.
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.
Steullet
Pascal
P
Center for Psychiatric Neurosciences, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Prilly-Lausanne, Switzerland. Pascal.Steullet@CHUV.ch
Lavoie
Suzie
S
Kraftsik
Rudolf
R
Guidi
Raffaella
R
Gysin
René
R
Cuénod
Michel
M
Do
Kim Q
KQ
D000818:Animals; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000633:toxicity; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency*; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000503:physiopathology
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D017448:Receptors, Dopamine D2; D019837:Ryanodine Receptor Calcium Release Channel; D019328:Buthionine Sulfoximine; D016202:N-Methylaspartate; D005978:Glutathione; D004298:Dopamine