Characteristics of the transport of the quaternary ammonium 1-methyl-4-phenylpyridinium by chromaffin granules.
1-Methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which induces Parkinson's disease in man, is a substrate of the monoamine uptake system of chromaffin granules. It is accumulated without chemical modification by bovine chromaffin granule membrane vesicles in the presence of ATP. The transport is saturable and is characterized by a Km value of 0.8 microM at pH 8.0, similar to that of serotonin (5-HT). Transport occurs through the monoamine transporter since it is competitively inhibited by 5-HT and since MPP+ competitively inhibits [3H]5-HT uptake. Moreover, [3H]MPP+ uptake is blocked by the monoamine transporter inhibitors tetrabenazine and reserpine. Finally, MPP+ efficiently displaces [3H]reserpine and [3H]dihydrotetrabenazine from their binding sites on the transporter. In the pH range 6-8, the Km for [3H]MPP+ uptake and the EC50 of MPP+ for the displacement of [3H]dihydrotetrabenazine decrease logarithmically with the pH. MPP+ is the first quaternary ammonium salt shown to be a substrate of the monoamine transporter and it has the same pH-dependency as monoamines.
Darchen
F
F
Institut de Biologie Physico-Chimique, C.N.R.S. UA 1112, Paris, France.
Scherman
D
D
Desnos
C
C
Henry
J P
JP
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active; D002417:Cattle; D002837:Chromaffin Granules / Q000378:metabolism*; D002838:Chromaffin System / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D011726:Pyridinium Compounds / Q000493:pharmacokinetics*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000493:pharmacokinetics; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000494:pharmacology
D011726:Pyridinium Compounds; D012701:Serotonin; C032811:dihydrotetrabenazine; D012110:Reserpine; D015655:1-Methyl-4-phenylpyridinium; D013747:Tetrabenazine