Friday, February 20, 2009
Q & A with Manojkumar Puthenveedu
Biological Sciences Newest Assistant Professor
Your research occurs at the interface of membrane trafficking, the cytoskeleton and neuronal signaling, which is an emerging forefront of neuronal cell biology. Can you describe the importance of this interplay, and why exactly it is an emerging forefront?
Almost every disease can be traced to a defect in how cells respond to signals; therefore, proper responses are extremely important. Cells must constantly integrate, adapt and control environmental signals in order to survive. One of the most complex examples of this integration, and the one I am interested in, is how neurons communicate with each other. Neuronal communication occurs when a cell releases signaling molecules into the extracellular medium. Then, these molecules bind receptor proteins present on the surface of adjacent neurons. Once bound, the receptors initiate signaling pathways in these neurons, which allow them to respond appropriately. I study how these receptor signaling pathways are maintained in normal cells, and how they are changed in abnormal conditions.
Since receptors need to be on the surface in order to see the signals, it makes logical sense that more receptors on the cell surface yield a stronger signal or better response. Membrane trafficking, with the help of the cytoskeleton, exquisitely controls this number by removing receptors from the cell surface through endocytosis and by adding more receptors on the cell surface through recycling and biosynthetic pathways.
Although we know that receptor trafficking plays a role in controlling signaling, we don’t know the specifics of this relationship or how trafficking itself is controlled. What exactly happens to signaling if you change endocytosis or other trafficking pathways? How does that affect neuronal behavior? Is trafficking in turn controlled by the same signaling pathways? These questions are all part of the interplay between receptor signaling, trafficking and neural biology.
What are some potential implications from your work?
I am interested in the role of membrane trafficking on drug addiction. The main receptors I work with are called opioid receptors, which recognize addictive drugs such as morphine and heroin. These receptors are essential for addiction to occur. However, opioid receptors are also the docking site for endorphins – endogenous chemicals that are responsible for blocking pain and for inducing feelings of pleasure. The difference between the addictive effects of drugs and endorphins may be in the membrane trafficking of the receptors after activation – whether they are internalized or remain on the cell surface. The main problem is that we don’t know exactly how endocytosis of these receptors is regulated in each case. One of the main goals in my first few years at Carnegie Mellon is to figure out if this regulation is different between morphine versus our endorphins, and heroin versus our endorphins. Then, I want to see if I can link this regulation to the propensity of these drugs to cause addiction.
This general research focus is also relevant in several other areas, including the cardiovascular system. The proteins mediating drug addiction are part of a large family of receptors called G protein-coupled receptors, or GPCRs, that respond to a wide variety of signals in our body. For instance, heart rate is controlled by similar receptors that respond to adrenaline, and abnormal signaling by these receptors is one of the main causes of heart attacks in our society. Even in the cardiovascular system, we don’t really know how exactly membrane trafficking affects signaling. This is another area that I’m interested in exploring, so depending upon what I find out I can easily move into cardiovascular research. I collaborate with a group at Stanford that strives to answer how adrenergic signaling is regulated in order to maintain cardiac function.
Can you tell us more about your current collaborations as well as your plans for future collaborations?
I also collaborate with a few neural biology groups at the University of California, San Francisco, including Lily Jan and Rob Edwards’s groups, as well as a group at Thomas Jefferson University. I look forward to collaborating with Carnegie Mellon Biological Sciences neuroscience faculty as well as faculty members Tina Lee and Adam Linstedt, whose work on trafficking parallels mine. I believe that Carnegie Mellon as a whole encourages collaboration and I look forward to being a part of that community. There are also several groups at University of Pittsburgh interested in GPCR signaling with whom I plan to collaborate.
In general, where is your field of research heading?
I believe the challenge is to integrate all available approaches. There are very few people like me who are working on the basic cellular level of drug addiction. There are numerous individuals working at the behavioral level as well as several groups working at the functional level studying electrophysiology in intact brains or brain slices. Over the next few years, I think the integration of all of these pockets of information will become extremely important. Each technique has its limitations and we need to tie the information together to have complete understanding. Also, recent technical advances, especially in cell biology, have made it possible for us to be able to ask and answer a completely different level of fundamental questions than we could have in the past.
How has having a Bachelor of Medicine, Bachelor of Surgery degree (the equivalent of a medical degree in the United States) influenced your research interest, in what way has it been helpful to your career and how do you think it will be advantageous to your new position at Carnegie Mellon?
It definitely gave me perspective on what is clinically relevant. It is also easier for me to understand from a practical sense where to direct my research. When I started in medicine, I quickly became aware that we know far less about our brain than what we know about other organs. The difference is clearly reflected in our treatment options for patients. This greatly influenced my decision when I chose my field of research. Therefore, I decided to enter an area where the fundamental principles are not very clear, yet directly pertain to a clinically relevant problem. Even though the research I am trained in and plan to do is very fundamental, I believe it really helps to understand the bigger picture.
As an alumnus of the Ph.D. in Biological Sciences program, what is the best part of coming back to Carnegie Mellon and Pittsburgh? Do you think it will help you in your new position?
I definitely think it will help. I really enjoyed my time at Carnegie Mellon and in Pittsburgh as a graduate student. What attracted me to Department of Biological Sciences as a graduate student is what attracted me to it now as a faculty member. It is a very interactive and small department, yet has good breadth of research. You get to know everyone very quickly, and since I am already familiar with many of the faculty members, I strongly believe it will be very easy to collaborate.