Photo by Elisabeth Fall.

First Appeared Friday, 19 April '02

Understanding the Chemical Language of the Brain

Part of a series of profiles about the faculty and staff working to help shape the UCSF Mission Bay campus or who will be among its first pioneers in scientific discovery.

If Mark von Zastrow has his way, we will one day be able to see inside living tissues as the brain's chemical messengers travel through the body like tiny spacecraft looking for their docking stations.

By using state-of-the-art imaging techniques and combining the fields of neurobiology and biochemistry, von Zastrow hopes to do nothing less than lead the way to new treatments of some of our most debilitating and costly psychiatric disorders, including addiction.

When he's not in the lab, von Zastrow, an associate professor of psychiatry, enjoys spending time with his wife, Junko, and their cats, Hoku and Tonto. He is an avid windsurfer, admitting that he sometimes plans lab work around wind conditions during sailing season. He also enjoys mountain biking on the many mid-Peninsula trails near his home in San Mateo.

Von Zastrow grew up in upstate New York in the small town of Niskayuna near Albany. He majored in biochemistry and wildlife ecology at Cornell University. "I always liked science. It was one of the few things I was good at in school." After college, von Zastrow earned his MD and a PhD in cell biology at Yale, moving onto Stanford University for his postdoctoral fellowship and residency. "As I studied, I got more and more interested in biochemical problems and realized that medicine was a great way to combine my interests in biochemistry, physiology and societal issues. It's an integrative thing."

According to colleagues, it's exactly that integrative approach that makes Von Zastrow's research on neurotransmitter receptors so groundbreaking. He is using biochemistry and neurobiology to study a class of receptors called G protein-coupled receptors, which includes receptors for opioids, dopamine and many other important signals in the brain. Many drugs used to treat psychiatric disorders, such as antidepressants, work by targeting these receptors. Regulation of these receptors has also been implicated in the biology behind addiction.

Von Zastrow is working to reveal the mechanisms by which these receptors function and are regulated. In particular, he is interested in how specific receptors get to the right parts of the cell to mediate their physiological effects. This is critical in neurons, where receptors can mediate different effects depending on their location. "We are looking at how the subcellular distribution of neurotransmitter receptors is regulated by physiological stimuli and by drugs." To do this, von Zastrow and his colleagues have defined sequences in receptors that act as "address signals" for receptors and have identified some of the cellular proteins that bind to them. But, to really understand the process, von Zastrow hopes to catch the movement of neurotransmitter receptors in action, something no one has ever done before. "We have been working over the last couple of years to develop methods of visualizing the movement of neurotransmitter receptors in living cells."

So far, by using standard methods, von Zastrow has found that many receptors detach from the cell surface and move to internal membranes when stimulated, but that this process varies depending on the neurotransmitter or drug involved. In the case of opioid receptors, this detachment mechanism is regulated differently depending on whether receptors are activated by opioid peptides, which are released by neurons and normally activate these receptors, or by drugs such as morphine, which are powerful analgesics with addictive properties. Von Zastrow is interested in what role drug-specific effects on receptor regulation play in the development of physical dependence and other features of addiction, such as craving.

Von Zastrow says he is anxiously awaiting his lab's move to the new Mission Bay campus because, once there, he and the members of his lab will be able to pick up the pace of their research and move faster in new directions. "Mission Bay offers great potential to set up more advanced facilities for live cell imaging. We are also looking forward to closer interactions with colleagues at Mission Bay who are developing new chemical methods that might be useful for manipulating specific mechanisms of receptor regulation in vivo."

One of von Zastrow's goals is to capture images of neurotransmitter receptors as they are activated by neurotransmitters and drugs in individual cells and in intact brain tissue. This, he says, will provide vital clues as to how defined trafficking mechanisms actually function in the living cell and the relationship of these dynamic events to cell signaling processes.

The move to Mission Bay will also put von Zastrow closer to his collaborators as they continue to lead the relatively new field of cellular neurobiology. "It's going to be an exciting opportunity for new ventures." Robert Edwards, one of von Zastrow's current collaborators, is eagerly awaiting the move. "Our interactions will only increase at Mission Bay, and we are already planning to purchase several new items of equipment jointly." Despite his prominence in the field, Edwards says, von Zastrow remains an unassuming and approachable person. "We really look forward to having him as a neighbor."

Edwards says he is also excited to see where von Zastrow's work will lead medical research. "Mark has found several very interesting features that have even more dramatic consequences than any of us might have imagined." By focusing on the movement of receptors, von Zastrow is studying very basic aspects of behavior and neuropsychiatric disease. "His focus on these important questions, his sophistication in the experimental approaches he uses to study them and his important contributions over a relatively short period of time have already made him a leader in the field."

In addition to their relevance to the action of drugs, the mechanisms von Zastrow is interested in have also been implicated in the basic biology behind learning and memory. In collaboration with Roger Nicoll, professor of cellular and molecular pharmacology, von Zastrow is looking at glutamate receptors found at synapses. The density of these receptors changes with the amount of activation the synapse experience. Von Zastrow hopes to perform imaging studies focused on these kinds of receptors, as well.

Eventually, von Zastrow hopes that these kinds of imaging studies move beyond the cells and into tissues and, later, into whole animals. "Mechanisms that regulate these receptors could be very important targets for the treatment psychiatric and neurological disorders in the future."

Camille Mojica Rey