Dopamine D(2) receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse.
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 D(2)-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D(2)-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D(2)-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D(2)-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 D(2)-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 D(2)-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 D(2)-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.
Oien
Derek B
DB
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045, USA.
Ortiz
Andrea N
AN
Rittel
Alexander G
AG
Dobrowsky
Rick T
RT
Johnson
Michael A
MA
Levant
Beth
B
Fowler
Stephen C
SC
Moskovitz
Jackob
J
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D008024:Ligands; D051150:Methionine Sulfoxide Reductases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*
D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D051150:Methionine Sulfoxide Reductases; D019204:GTP-Binding Proteins; D004298:Dopamine