July 1, 2011 — Picture a juicy steak, hot off the grill (or, if you prefer, a marinated slice of tofu). Just imagining it makes your mouth water, doesn't it?

That secretion process you're experiencing is a common activity of the cells throughout the body, not only in the mouth. Cells secrete chemicals, such as hormones, as a way to talk, in effect, to other cells. Cells secrete to function, and the entire organism, the body, functions partly through the important process of secretion, essential to growth, mood, digestion, even reproduction.

In neurons, the cells of the central nervous system, a similar process occurs – secretion of neurotransmitters from one cell to the next. Neurotransmitters are chemicals that transmit signals from a neuron to a target cell. Chemicals, such as serotonin, which regulates mood, are neurotransmitters that send critical messages from cell to cell, serving an essential function to overall well being.

This process of message transmission, which is regulated by a complex machinery of specialized protein molecules, is a poorly understood activity of cells. And sometimes that process, possibly due to a mutation, is altered, or interrupted, resulting in disease.

Three University of Virginia researchers, in three departments at two schools – the College of Arts & Sciences and the School of Medicine – are working to better understand the mechanism of neurotransmitter release, the molecular pathways that allow neural cells to pass crucial chemicals from cell to cell.

"We're studying how this happens, how neurons release chemicals into the junction between one neuron and another," said Lukas Tamm, professor of molecular physiology and biological physics and lead investigator on what is now an $11 million grant from the National Institute of General Medical Sciences, part of the National Institutes of Health.

Tamm and his co-investigators, Dave Cafiso, professor of chemistry, and David Castle, professor of cell biology, are collaborating with Reinhard Jahn at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, and have just received a five-year, $6 million contract renewal to continue this work, after having recently successfully completed initial investigations on a previous six-year, $5 million program project grant from NIGMS.

The work has implications for the possible future creation of drugs that could directly target neural cell mutations attributed to many neurological, mental health and neurodegenerative diseases, including epilepsy, schizophrenia, bipolar disorder, Huntington's, Parkinson's and Alzheimer's diseases.

"If we can understand the mechanism that allows neurons to release chemicals from one cell to the other, then, possibly, drugs eventually could be designed to facilitate or block this activity, as needed, even repair it if it's defective," said Cafiso, who is an expert in magnetic resonance imaging of molecules.

Tamm and Cafiso said many currently used drugs are designed to take a scattergun approach, alleviating some problems while possibly, inadvertently, causing others. Many drug side effects and unwanted outcomes are the result of this unfocused targeting. So gaining a clear picture of the molecular mechanisms that underlie chemical transfer between cells would be highly beneficial to hitting the process directly at the transaction point.

That point between cells in the nervous system, the junction that allows neurons to pass a signal to another cell, is called synapse. Synapses allow neurons to pass signals between cells, including non-neural cells. When you want to move your arm, for example, the brain signals through the neurons to the appropriate muscles to allow the movement. Synapses make it happen by passing the signal from cell to cell including at the end – in a neuromuscular junction – to the muscle cells; and all of this happens in a flash.

But a complicated interaction occurs between those cells as the signal passes. Each cell has a wall, a membrane that must open, in milliseconds, to release or to accept the signal. The neurotransmitters are actually packaged in a physical structure on the nanoscale, a presynaptic vesicle that has its own membrane. Whenever a neuron signals, a bunch of these vesicles release their contents by a mechanical process of fusion – a "snare" system that allows the presynaptic vesicles to dock at the cell membranes and unload their neurotransmitter cargo.

The U.Va./Max Planck team, with the help of additional colleagues at both institutions, are looking directly at those membrane proteins at the junction of the interactions. To do this, they use a multidisciplinary team of investigators, taking a multipronged approach. The team includes cell biologists, biochemists, structural biologists and biophysicists. They are studying the fusion process with a variety of techniques, including high-resolution optical and magnetic resonance imaging of the process as it happens.

"It is possible to gain the insight we're seeking only through a multidisciplinary approach, bringing together an array of people with different skills and expertise to tackle a very complex and important problem," Cafiso said.

The contract from NIGMS is a program project grant, specifically awarded to diverse groups of researchers working together with multiple techniques on a common problem. Tamm and Cafiso noted that U.Va. has particular strengths in research on cellular membranes, which helped the team win the grant renewal.

"We have an outstanding collaboration on this project because we have core strengths at U.Va. in structural and membrane biology with more than a dozen faculty members using diverse but complementary techniques," Tamm said. "And in the long run, this helps us recruit additional strong faculty to tackle the really big problems."

Tamm, Cafiso and their team hope that eventually, as they gain a clearer picture of the mechanism that allows the release of neurotransmitters, they will be able to work with applied medical researchers on a quest to create drugs that could directly treat the root causes of some disease.