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Plos One : Inhibition of Dopamine Transporter Activity by G Protein Βγ Subunits, Volume 8

By Mothet, Jean-pierre

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Book Id: WPLBN0003950672
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos One : Inhibition of Dopamine Transporter Activity by G Protein Βγ Subunits, Volume 8  
Author: Mothet, Jean-pierre
Volume: Volume 8
Language: English
Subject: Journals, Science, Medical Science
Collections: Periodicals: Journal and Magazine Collection (Contemporary)
Publication Date:
Publisher: Plos

Description : Uptake through the Dopamine Transporter (DAT) is the primary mechanism of terminating dopamine signaling within the brain, thus playing an essential role in neuronal homeostasis. Deregulation of DAT function has been linked to several neurological and psychiatric disorders including ADHD, schizophrenia, Parkinson’s disease, and drug addiction. Over the last 15 years, several studies have revealed a plethora of mechanisms influencing the activity and cellular distribution of DAT: suggesting that fine-tuning of dopamine homeostasis occurs via an elaborate interplay of multiple pathways. Here, we show for the first time that the bc subunits of G proteins regulate DAT activity. In heterologous cells and brain tissue, a physical association between Gbc subunits and DAT was demonstrated by co-immunoprecipitation. Furthermore, in vitro pull-down assays using purified proteins established that this association occurs via a direct interaction between the intracellular carboxy-terminus of DAT and Gbc. Functional assays performed in the presence of the non-hydrolyzable GTP analog GTP-c-S, Gbc subunit overexpression, or the Gbc activator mSIRK all resulted in rapid inhibition of DAT activity in heterologous systems. Gbc activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from mouse striatum as measured by high-speed chronoamperometry in vivo. Gbc subunits are intracellular signaling molecules that regulate a multitude of physiological processes through interactions with enzymes and ion channels. Our findings add neurotransmitter transporters to the growing list of molecules regulated by G-proteins and suggest a novel role for Gbc signaling in the control of dopamine homeostasis.


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