Regulated Membrane Trafficking of Variant Dopamine Receptors Associated with Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
von Zastrow, Mark, MD, PhD

Dopamine is an important neurotransmitter that binds to a specific class of receptor proteins present on the surfaces of neurons. Excessive activity of these receptors is thought to underlie many of the symptoms of Tourette Syndrome (TS). Indeed, drugs that reduce dopamine receptor activation are a mainstay in the medical therapy of TS. Recent studies in many labs have made the interesting discovery that there is a great deal of structural diversity among the dopamine receptors. Dopamine receptors were once classified as either D1 or D2 types, according to differences in pharmacology and basic signaling properties. We now appreciate that the D2 class of receptors alone is comprised of over 6 different receptor molecules, which vary in their structure and are expressed in different regions of the brain. The functional importance of this receptor diversity is an important area of basic research, and may have great importance for understanding the basic biology of TS. Perhaps the strongest evidence for this idea comes from the field of human genetics, where researchers have discovered that individuals inherit and express different variant forms of dopamine receptors. Also, we have learned that the inheritance of certain receptor variants appears to be associated with an increased prevalence of TS. F Despite these provocative findings, it has been difficult to understand just how variant dopamine receptors actually differ in function. This is a critical question that must be answered in order to understand any mechanistic relationship between dopamine receptor diversity and TS. So far, most studies of this question have focused on looking for differences between receptors in pharmacology or basic signaling properties. Relatively less is known about how variant dopamine receptors are regulated, even though it is well-established that dopamine receptors are extensively regulated physiologically. The basic hypothesis underlying our work is that variant dopa-mine receptors differ fundamentally in how they are regulated physiologically in intact cells. We are looking specifically at regulatory mechanisms that control the number and localization of receptors within cells. A reason for studying these mechanisms in particular is that several studies suggest that TS is associated with dysregulation of the number and localization of dopamine receptor variants in the brain. We are performing studies of dopamine receptor cell biology using cloned cell lines grown in the laboratory. These cell lines allow us to study mechanisms that regulate dopamine receptors in great detail. We have observed that D1 and D2 dopamine receptors differ substantially in their localization within cells, both at steady state in unstimulated cells, and in cells activated by dopamine. Our current studies are extending these initial studies to variant D2 and D4 dopamine receptors that have been implicated in TS by genetic studies. Our goal is both to contribute to the basic science understanding of precisely how dopamine receptors are regulated, and to look specifically for differences in regulation that may provide a clue to how variant dopamine receptors could actually cause or promote the development of TS in patients. If we are successful, it may be possible to design new therapies for TS that are targeted directly at cellular mechanisms that mediate important variant-specific differences in receptor regulation. Support from the Tourette Syndrome Association will help us greatly in moving ahead with these studies. Mark von Zastrow, M.D., Ph.D. University of California San Francisco, CA Award: $40,000 Tourette Association of America Inc. – Research Grant Award 1997