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Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse
Oien, Derek B. ; Ortiz, Andrea Naomi ; Rittel, Alexander G. ; Dobrowsky, Rick T. ; Johnson, Michael A. ; Levant, Beth ; Fowler, Stephen C. ; Moskovitz, Jackob
Oien, Derek B.
Ortiz, Andrea Naomi
Rittel, Alexander G.
Dobrowsky, Rick T.
Johnson, Michael A.
Levant, Beth
Fowler, Stephen C.
Moskovitz, Jackob
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Abstract
Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D2-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D2-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D2-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D2-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D2-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D2-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.
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Date
2010-07
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Wiley
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Keywords
Dopamine, Dopamine receptor, Locomotor activity, Methionine oxidation, Oxidative stress, Post-translation modification
Citation
Oien, D. B., Ortiz, A. N., Rittel, A. G., Dobrowsky, R. T., Johnson, M. A., Levant, B., … Moskovitz, J. (2010). Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse. Journal of Neurochemistry, 114(1), 51–61. http://doi.org/10.1111/j.1471-4159.2010.06721.x