Selective MPP+ uptake into synaptic dopamine vesicles: possible involvement in MPTP neurotoxicity

Abstract

1 In the present study we provide evidence for a saturable, Mg2+/ATP-and temperature-dependent, tetrabenazine-, dopamine-, and amphetamine-sensitive uptake of l-methyl-4-phenylpyridinium ion (MPP+) in synaptic vesicles from mouse striatum. 2 Similarity in the properties of the vesicular uptake suggests that in the striatum dopamine and MPP+ share the vesicular carrier. 3 The presence of MPP+ vesicular uptake in dopamine-rich regions such as striatum, olfactory, tubercles and hypothalamus, as well as its absence in cerebellum, cortex and pons-medulla, suggest that monoamine vesicular carriers differ between highly and poorly dopamine-innervated regions. 4 The restriction of active MPP+ uptake to the dopaminergic regions, which reflects the previously shown distribution of [3H]-MPP+ binding sites in mouse brain membranes, indicates MPP+ as a marker of the vesicular carrier for dopamine in dopaminergic neurones. 5 A role in MPP+ neurotoxicity is suggested for this region-specific, vesicular storage of the toxin.

The Parkinsonism-inducing Drug 1-Methyl-4-phenylpyridinium Triggers Intracellular Dopamine Oxidation

“…Studies utilizing VMAT2 knock-out mice have confirmed the notion that DA is stored primarily in synaptic vesicles (76). Because MPP ϩ has a high affinity for VMAT2 (21)(22)(23) and can be taken up into catecholaminergic vesicles (24,77,78), it conceivably redistributes DA from its storage sites to the cytosol. This hypothesis was proposed more than a decade ago, although subsequent studies (e.g.…”

Vesicular monoamine transporter 2: Role as a novel target for drug development

“…17 N -Methyl-4-phenylpyridinium (MPP + ), the active toxic metabolite of MPTP, is a substrate for VMAT2. [23][24][25][26][27] VMAT2 sequesters MPP + in synaptic vesicles and thereby protects catecholamine-containing neurons from MPP + -induced toxicity and degeneration. 3 , 28-32 CHO cells, which are normally sensitive to MPP + toxicity, because they lack a plasma membrane amine transporter, can be made relatively insensitive to MPP + toxicity by transfection with VMAT complementary DNA.…”

Animal Models of Parkinson’s Disease Induced by Toxins and Genetic Manipulation

“…Once inside DAergic neurons, MPP+ can accumulate in mitochondria and impair mitochondrial respiration by inhibiting complex I in the electron transport chain (Nicklas, et al, 1985;Ramsay & Singer, 1986), which induces the generation of reactive oxygen species (ROS). MPP+ can also bind to vesicular monoamine transporters (VMATs), which help move selected materials into synaptic vesicles containing DA (Del Zompo et al, 1993). MPP+ can also remain in the cytoplasm and interact with cytosolic enzymes (Klaidman et al, 1993).…”