Dopamine Transporter Activity Is Modulated by α-Synuclein

Abstract

Background: DAT regulates dopamine neurotransmission in the brain. Results: ␣-Synuclein influences DA efflux and membrane microdomain distribution of DAT. Conclusion: DAT activation recruits ␣-synuclein to the membrane, which in turn influences dopamine neurotransmission. Significance: Understanding the mechanisms associated with ␣-synuclein regulation of DAT may reveal disease-modifying targets for the treatment of pathologies associated with DA dysregulation.

Alpha-synuclein modulates dopamine neurotransmission

“…Therefore, the alpha-synuclein mediated decrease in dopamine uptake alone, might not be the sole underlying mechanism for the elevated extracellular dopamine levels. In a recent study, Butler et al have shown alpha-synuclein overexpression increases the DAT-mediated, nomifensine-sensitive basal dopamine efflux at resting membrane potential [18]. These reports are in agreement with the emerging consensus that alpha-synuclein regulates dopamine neurotransmission by influencing the action potential independent dopamine release via DAT.…”

“…A recent study by Ronzitti et al suggests that elevation of extracellular monomeric form of alpha-synuclein mediates Ca 2+ increase via the Cav2.2 N-type Ca 2+ channel in cortical neurons [71], confirming Adamczyk’s report [68]. The alpha-synuclein regulation of Ca 2+ channels in striatal slices has been shown to stimulate dopamine release, potentially via both classical neurotransmission mechanism and efflux of dopamine via DAT [18, 71]. Ronzitti et al postulated that dysregulation of lipid rafts by alpha-synuclein overexpression causes a shift in Cav2.2 channels from cholesterol rich to cholesterol poor membrane microdomains thus altering Cav2.2 function as well as dopamine release.…”

“…However, reminiscent to DAT KO animals [42–46], alpha-Syn −/− mice exhibited a reduction in striatal dopamine content and inhibition of dopamine-dependent locomotor response to amphetamine, a psychostimulant known to increase locomotion via a DAT-dependent mechanism [47, 48]. These findings strongly support the hypothesis that alpha-synuclein is involved in regulation of dopamine neurotransmission [17, 18, 49, 50]. Alpha-synuclein regulation of dopaminergic neurons was further studied by Garcia-Reitboeck et al in mice carrying a spontaneous deletion of the alpha-synuclein locus [51].…”

“…It is well established that alpha-synuclein co-immunoprecipitates with DAT in transfected cells, rat primary mesencephalic dopaminergic neurons, and striatal tissue [18, 102, 123]; however, the consequence of this interaction on dopamine uptake via DAT is less understood. While Chadchankar’s group reported a decrease in dopamine uptake in the dorsal striatum of alpha-synuclein knockout mice, in vitro and in vivo studies suggest increased alpha-synuclein levels decreased DAT-mediated dopamine uptake [17, 102].…”

“…Since DAT operates in multiple modes (i.e., forward, reverse, and channel mode), an increase in dopamine efflux may affect the measured net dopamine uptake. Recently two different studies have shown that increased alpha-synuclein at or near the surface membrane enhances the interaction between DAT and alpha-synuclein, thus altering the ionic conductance of the transporter that can uniquely affect the excitability of dopaminergic neurons and thus dopamine neurotransmission [17, 18]. …”