Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Inhibition of Dopamine Transporter Activity by G Protein βγ Subunits

Garcia-Olivares, J and Torres-Salazar, D and Owens, WA and Baust, T and Siderovski, DP and Amara, SG and Zhu, J and Daws, LC and Torres, GE (2013) Inhibition of Dopamine Transporter Activity by G Protein βγ Subunits. PLoS ONE, 8 (3).

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (1MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

Abstract

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 βγ subunits of G proteins regulate DAT activity. In heterologous cells and brain tissue, a physical association between Gβγ 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 Gβγ. Functional assays performed in the presence of the non-hydrolyzable GTP analog GTP-γ-S, Gβγ subunit overexpression, or the Gβγ activator mSIRK all resulted in rapid inhibition of DAT activity in heterologous systems. Gβγ activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from mouse striatum as measured by high-speed chronoamperometry in vivo. Gβγ 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 Gβγ signaling in the control of dopamine homeostasis. © 2013 Garcia-Olivares et al.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Garcia-Olivares, J
Torres-Salazar, D
Owens, WA
Baust, Ttbcst3@pitt.eduTBCST3
Siderovski, DP
Amara, SG
Zhu, J
Daws, LC
Torres, GEgtorres@pitt.eduGTORRES
Date: 26 March 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0059788
Schools and Programs: School of Medicine > Neurobiology
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Other ID: NLM PMC3608556
PubMed Central ID: PMC3608556
PubMed ID: 23555781
Date Deposited: 22 Apr 2013 15:59
Last Modified: 26 Jan 2019 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/18318

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item