Abstract
Regulator of G-Protein Signaling 6 Controls Dopamine Reuptake Via the Dopamine Transporter (Abstract ID: 224563)
The Journal of pharmacology and experimental therapeutics, Vol.393(5), 104024
05/2026
DOI: 10.1016/j.jpet.2026.104024
Abstract
Parkinson's disease (PD), the second most common neurodegenerative disorder and most common movement disorder in humans, is characterized by progressive loss of dopamine (DA) producing neurons in the substantia nigra pars compacta (SNc), which send their axonal projections to the dorsal stratum (DS). Structural impairment in this pathway leads to PD symptoms, including bradykinesia and gait disturbances. However, the pathogenic mechanisms driving PD remain poorly understood. Regulator of G protein Signaling 6 (RGS6), expressed in DA neurons in the SNc of mice and humans, is downregulated in the SNc of PD patients. Global RGS6 depletion in mice triggers age-dependent loss of DA neurons in the SNc, aberrant accumulation of α-synuclein, and L-DOPA sensitive PD-like motor deficits. Here, we identify a novel RGS6 effector in DA neurons, the dopamine transporter (DAT), which mediates rapid clearance of extracellular DA. Importantly, RGS6 gene deletion in mice triggers an increase in DAT immunoreactivity in the SNc and DS. Ex vivo brain slices isolated from RGS6 knockout mice (KO) also display region- and sex-dependent DAT hyperactivity. In transfected HEK293T cells, RGS6 formed a co-precipitable complex with DAT, decreased DAT surface expression, and impaired [3H]-DA uptake. Ongoing work seeks to establish if RGS6 directly inhibits DAT or influences DAT activity indirectly by acting as a GTPase-activating protein (GAP) for Gαi/o coupled DA D2 autoreceptors (D2ARs). Together, these data indicate that RGS6 may protect SNc neurons from degeneration by inhibiting DAT, which has been shown to accelerate the accumulation of cytotoxic DA metabolites and drive DA neuron degeneration.
Details
- Title: Subtitle
- Regulator of G-Protein Signaling 6 Controls Dopamine Reuptake Via the Dopamine Transporter (Abstract ID: 224563)
- Creators
- Danlin Liu - University of IowaZili Luo - University of IowaJianqi Yang - University of Iowa, Neuroscience and PharmacologyDingxi Li - University of IowaJacob Bernholtz - University of Iowa, Neuroscience and PharmacologyNathan T. Fassett - University of IowaMengcheng Guo - University of IowaRory Fisher - University of IowaAdele Stewart - University of Iowa, Neuroscience and Pharmacology
- Resource Type
- Abstract
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.393(5), 104024
- DOI
- 10.1016/j.jpet.2026.104024
- ISSN
- 0022-3565
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 05/2026
- Academic Unit
- Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9985163946902771
Metrics
1 Record Views