Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The Dopamine Transporter

23.07.2014

Researchers use TACC's Stampede supercomputer to study a common link between addiction and neurological disease

Recent published research in the Journal of Clinical Investigation demonstrates how changes in dopamine signaling and dopamine transporter function are linked to neurological and psychiatric diseases, including early-onset Parkinsonism and attention deficit hyperactivity disorder (ADHD).


An illustration of the binding site for cocaine in the dopamine transporter.


Because of the complexity of the human dopamine transporter structure, the models used to investigate the effects of drugs of abuse and neurological disorders are based on similar crystal structures from the bacterial transporter, LeuT (grey) and the Drosophila melanogaster fly (red). This image shows the superimposition of those molecular models and their binding sites and the location of two of the mutations in the dopamine transporter identified in the published work.

"The present findings should provide a critical basis for further exploration of how dopamine dysfunction and altered dopamine transporter function contribute to brain disorders" said Michelle Sahai, a postdoctoral associate at the Weill Cornell Medical College of Cornell University, adding "it also contributes to research efforts developing new ways to help the millions of people suffering."

Sahai is also studying the effects of cocaine, a widely abused substance with psychostimulant effects that targets the dopamine transporter. She and her colleagues expect to release these specific findings within the next year.

Losing Control

Dopamine is a neurotransmitter that plays an important role in our cognitive, emotional, and behavioral functioning. When activated from outside stimuli, nerve cells in the brain release dopamine, causing a chain reaction that releases even more of this chemical messenger.

To ensure that this doesn't result in an infinite loop of dopamine production, a protein called the dopamine transporter reabsorbs the dopamine back into the cell to terminate the process. As dopamine binds to its transporter, it is returned to the nerve cells for future use.

However, cocaine and other drugs like amphetamine, completely hijack this well-balanced system.

"When cocaine enters the bloodstream, it does not allow dopamine to bind to its transporter, which results in a rapid increase in dopamine levels," Sahai explained.

The competitive binding and subsequent excess dopamine is what causes euphoria, increased energy, and alertness. It also contributes to drug abuse and addiction.

To further understand the effects of drug abuse, Sahai and other researchers in the Harel Weinstein Lab at Cornell are delving into drug interactions on a molecular level.

Using supercomputer resources, she is able to observe the binding of dopamine and various drugs to a 3D model of the dopamine transporter on a molecular level. According to Sahai, the work requires very long simulations in terms of microseconds and seconds to understand how drugs interact with the transporters.

Through the Extreme Science and Engineering Discovery Environment (XSEDE), a virtual cyberinfrastructure that provides researchers access to computing resources, Sahai performs these simulations on Stampede, the world's 7th fastest supercomputer, at the Texas Advanced Computing Center (TACC).

"XSEDE-allocated resources are fundamental to helping us understand of how drugs work. There's no way we could perform these simulations on the machines we have in house. Through TACC as an XSEDE service provider, we can also expect an exponential increase in computational results, and good customer service and feedback."

Ultimately, Sahai's research will contribute to an existing body of work that is attempting to develop a cocaine binding inhibitor without suppressing the dopamine transporter.

"If we can understand how drugs bind to the dopamine transporter, then we can better understand drug abuse and add information on what's really important in designing therapeutic strategies to combat addiction," Sahai said.

A Common Link in the Research

While Sahai is still working to understand drug abuse, her simulations of the dopamine transporter have contributed to published research on Parkinson's disease and other neurological disorders.

In a collaborative study with the University of Copenhagen, Copenhagen University Hospital, and other research groups in the U.S. and Europe, researchers revealed the first known link between de novo mutations in the dopamine transporter and Parkinsonism in adults.

The study found that mutations can produce typical effects including debilitating tremors, major loss of motor control, and depression. The study also provides additional support for the idea that dopamine transporter mutations are a risk factor for attention deficit hyperactivity disorder (ADHD).

After identifying the dopamine transporter as the mutated gene linked to Parkinson's, researchers once again turned to the Harel Weinstein Lab due to its long-standing interest and investment in studying the human dopamine transporter.

Sahai's simulations using XSEDE and TACC's Stampede supercomputer supported clinical trials by offering greater insight into how the dopamine transporter is involved in neurological disorders.

"This research is very important to me," Sahai said. "I was able to look at the structure of the dopamine transporter on behalf of experimentalists and understand how irregularities in this protein are harming an actual person, instead of just looking at something isolated on a computer screen."

While there is currently no cure for Parkinson's disease, a deeper understanding of the specific mechanisms behind it will help the seven to ten million people afflicted with the disease.

"Like my work on drug abuse, the end goal is thinking about how we can help people. And it all comes back to drug design," Sahai said.

Makeda Easter,
Science and Technology Writer

 

 
 
 
The Texas Advanced Computing Center (TACC) at The University of Texas at Austin is one of the leading centers of computational excellence in the United States. The center's mission is to enable discoveries that advance science and society through the application of advanced computing technologies. To fulfill this mission, TACC identifies, evaluates, deploys, and supports powerful computing, visualization, and storage systems and software. TACC's staff experts help researchers and educators use these technologies effectively, and conduct research and development to make these technologies more powerful, more reliable, and easier to use. TACC staff also help encourage, educate, and train the next generation of researchers, empowering them to make discoveries that change the world.

Faith Singer-Villalobos | Eurek Alert!
Further information:
https://www.tacc.utexas.edu/news/feature-stories/2014/the-dopamine-transporter

Further reports about: Computing Parkinson's TACC XSEDE cocaine dopamine drugs mutations neurological technologies

More articles from Life Sciences:

nachricht An evolutionary heads-up – The brain size advantage
22.05.2015 | Veterinärmedizinische Universität Wien

nachricht Endocrine disrupting chemicals in baby teethers
21.05.2015 | Goethe-Universität Frankfurt am Main

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: IoT-based Advanced Automobile Parking Navigation System

Development and implementation of an advanced automobile parking navigation platform for parking services

To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...

Im Focus: First electrical car ferry in the world in operation in Norway now

  • Siemens delivers electric propulsion system and charging stations with lithium-ion batteries charged from hydro power
  • Ferry only uses 150 kilowatt hours (kWh) per route and reduces cost of fuel by 60 percent
  • Milestone on the road to operating emission-free ferries

The world's first electrical car and passenger ferry powered by batteries has entered service in Norway. The ferry only uses 150 kWh per route, which...

Im Focus: Into the ice – RV Polarstern opens the arctic season by setting course for Spitsbergen

On Tuesday, 19 May 2015 the research icebreaker Polarstern will leave its home port in Bremerhaven, setting a course for the Arctic. Led by Dr Ilka Peeken from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) a team of 53 researchers from 11 countries will investigate the effects of climate change in the Arctic, from the surface ice floes down to the seafloor.

RV Polarstern will enter the sea-ice zone north of Spitsbergen. Covering two shallow regions on their way to deeper waters, the scientists on board will focus...

Im Focus: Gel filled with nanosponges cleans up MRSA infections

Nanoengineers at the University of California, San Diego developed a gel filled with toxin-absorbing nanosponges that could lead to an effective treatment for skin and wound infections caused by MRSA (methicillin-resistant Staphylococcus aureus), an antibiotic-resistant bacteria. This "nanosponge-hydrogel" minimized the growth of skin lesions on mice infected with MRSA - without the use of antibiotics. The researchers recently published their findings online in Advanced Materials.

To make the nanosponge-hydrogel, the team mixed nanosponges, which are nanoparticles that absorb dangerous toxins produced by MRSA, E. coli and other...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International symposium: trends in spatial analysis and modelling for a more sustainable land use

20.05.2015 | Event News

15th conference of the International Association of Colloid and Interface Scientists

18.05.2015 | Event News

EHFG 2015: Securing health in Europe. Balancing priorities, sharing responsibilities

12.05.2015 | Event News

 
Latest News

Mesoporous Particles for the Development of Drug Delivery System Safe to Human Bodies

22.05.2015 | Materials Sciences

Computing at the Speed of Light

22.05.2015 | Information Technology

Development of Gold Nanoparticles That Control Osteogenic Differentiation of Stem Cells

22.05.2015 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>