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 Chains of nanogold – forged with atomic precision
23.09.2016 | Suomen Akatemia (Academy of Finland)

nachricht Self-assembled nanostructures hit their target
23.09.2016 | King Abdullah University of Science and Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

Im Focus: New laser joining technologies at ‘K 2016’ trade fair

Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.

K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

Using mathematical models to understand our brain

16.09.2016 | Event News

 
Latest News

Custom-tailored strategy against glioblastomas

26.09.2016 | Health and Medicine

Cooling buildings with solar heat

26.09.2016 | Power and Electrical Engineering

Chains of nanogold – forged with atomic precision

23.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>