Inhibition by arachidonic acid and other fatty acids of dopamine uptake at the human dopamine transporter.
It is known that arachidonic acid, in addition to promoting release of dopamine, can inhibit its transport. The present study provides preliminary information on structure-activity relationships for uptake inhibition by rotating disk voltammetry in human embryonic kidney-293 cells expressing the human dopamine transporter. Except for anandamide, all other fatty acids studied at a pretreatment concentration of 80 microM caused significant reductions in Vmax but not Km. Increasing saturation of the hydrocarbon tails (partial saturation: oleic acid, linoleic acid; full saturation: arachidic acid, stearic acid, stearic acid ethyl ester) removed inhibitory activity incrementally, suggesting a role for cis-unsaturation (folding/bending of hydrocarbon tails). The relative lack of effect of 5,8,11,14-eicosatetraynoic acid also supports the idea that less linear structures are less inhibitory on dopamine uptake. Esterification of the free carboxylic group (arachidonic acid ethyl ester) prevented most of the inhibitory activity, arguing against mere membrane lipid disruption. Finally, the endogenous cannabinoid anandamide greatly reduced uptake Vmax accompanied by a small decrease in Km, a potentially important effect on dopaminergic neurotransmission.
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Box 1649, Peoria, IL 61656-1649, USA.
Nianhang
N
Chen
Michael
M
Appell
Janet L
JL
Berfield
Maarten E A
ME
Reith
D016718:Arachidonic Acid / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D015777:Eicosanoids / Q000378:metabolism; D004566:Electrodes; D063388:Endocannabinoids; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008562:Membrane Glycoproteins; D008563:Membrane Lipids / Q000737:chemistry; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D002264:Carboxylic Acids; D050483:Dopamine Plasma Membrane Transport Proteins; D015777:Eicosanoids; D063388:Endocannabinoids; D005227:Fatty Acids; D006838:Hydrocarbons; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D016718:Arachidonic Acid; C078814:anandamide; D004298:Dopamine