Getting your Trinity Audio player ready...

Dr. Bin Liu, associate professor at The Hormel Institute, University of Minnesota, has co-authored a recently published paper in Nature.

The paper, entitled “Structural insights into vesicular monoamine storage and drug interactions,” presents the first series of cryoEM structures of proteins known as vesicular monoamine transporters (VMATs) and sheds new light on their mechanisms, laying a crucial foundation for the development of more effective treatment options for neurodegenerative diseases (such as Parkinson’s disease and Alzheimer’s disease) and substance addiction.

Monoamines are key transmitters of neurological, endocrinological, and immunological functions that include motor control, cognitive functions such as processing memory and emotions, and modulating blood pressure and immune responses. Dopamine, serotonin, and histamines are just a few examples of the essential monoamine transmitters that can be found within our bodies.

A type of protein known as a vesicular monoamine transporter (VMAT) stores these monoamines in a cell’s storage vesicles, where the monoamines await controlled release to send chemical messages to neurons as needed. VMATs are also able to enrich monoamines by  10,000-fold, and they help protect against neuronal damage by sequestering neurotoxins like MPP+, which induces Parkinson’s disease. Amphetamine-related drugs are also imported by VMATs, leading to monoamine release and psychostimulation.

“VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension, and drug addiction,” Liu said. “In vivo imaging of VMATs enables early detection and progression of Parkinson’s disease, Alzheimer’s disease, schizophrenia, and drug addiction.”

While much is known about VMATs, the underlying mechanisms of the protein — and how they interact with monoamines and certain drugs—have remained a mystery, including::

• What mechanisms make VMATs’ extraordinary storage capabilities possible?

• What mechanisms make VMATs’ broad, yet selective ability to recognize amine-containing substrates possible?

• How do certain therapeutic and illicit drugs interact with VMATs?

This research, co-led by Dr. Weikai Li at Washington University in St. Louis, Missouri, and Liu at the University of Minnesota, used The Hormel Institute’s cryoEM facility to determine the structures of VMATs—both alone and in interaction with other substrates and compounds—which unlocked new information about some of these questions.

The paper publishes eight of the first high-resolution renderings of the structures of human VMAT1.

Researchers discovered:

• Monoamine binds to a common pocket on the VMAT that also allows MPP+ and amphetamine to bind to it.

• The mechanism that allows for accumulation and storage of monoamines.

• Unintended depletion of monoamines is prevented by protonation (the addition of a proton), which disrupts monoamine binding but induces a vesicular-open state for import of additional monoamines.

• Reserpine mimics the protonated state mentioned above, and it is also associated with a common variation of VMAT1 that is associated with increased risk for schizophrenia and bipolar disorder.

“We believe our findings will be of interest to a very broad audience, including neurologists, immunologists, endocrinologists, pharmacologists, membrane biologists, and structural biologists, as well as clinical researchers and doctors,” Liu said.

You can read the paper here: https://www.nature.com/articles/s41586-024-07290-7.