Modulation of D1-like dopamine receptor function by aldehydic products of lipid peroxidation.
Growing evidence indicates that aldehydic products of lipid peroxidation play an important role in the pathophysiology of neurodegenerative disorders such as Parkinson's disease. In the present study, modulation of D1-like receptor binding and function by saturated alkanals and unsaturated alkenals, 4-hydroxynonenal (4-HNE) and trans-2-nonenal (nonenal), was examined in rat striatal membranes. The 4-HNE and nonenal were most effective in modulating both the specific D1-like receptor binding and function as measured by adenylate cyclase activation. Inactivation of receptor binding and the depression of adenylate cyclase activity were partially prevented by protection of the D1/D5-receptor with the agonist (R)-SKF 38393 or the specific antagonist SCH 23390. 4-HNE inhibited adenylate cyclase activation by Gpp (NH)p and forskolin, indicating the modulation of Gsalpha and the catalytic subunit of adenylate cyclase, respectively. Our data suggests that aldehydic products of lipid peroxidation can directly modulate the binding and functional properties of D1/D5 receptors, as well as effector proteins within their signaling pathway.
Shin
Yangmee
Y
Department of Pediatrics, Georgetown University Medical Center, 3970 Reservoir Road, N.W., 20057, Washington, DC, USA.
White
Beatrix H
BH
Uh
Misook
M
Sidhu
Anita
A
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000493:pharmacokinetics; D000262:Adenylyl Cyclases / Q000378:metabolism; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*; D050641:Receptors, Dopamine D5
C049558:8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol; D000447:Aldehydes; D001552:Benzazepines; D015853:Cysteine Proteinase Inhibitors; C493605:DRD5 protein, human; D018492:Dopamine Antagonists; C493607:Drd5 protein, rat; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C027576:4-hydroxy-2-nonenal; D004298:Dopamine