Electrical signalling in the human body plays a role in nearly all of the processes which allow us to survive. Conscious thought, unconscious regulation of bodily functions, memory, and muscle movements are just a few of the events in which the control of electrical activity is essential. I believe that by gaining a better understanding of the biophysical principals underlying the activity of the proteins involved in electrical signialing, we will be better able to understand these bodily processes, and to treat the diseases that result from their misregulation.

With this motivation in mind, my biological research has focused on two different classes of proteins involved in electrical signaling processes.

 

Voltage-Sensitive Phosphatases (VSPs)

 

For the latter half of the last century, voltage-sensitive ion channels have been studied for their ability to affect electrical signals in cells. These remarkable proteins essentially act as molecular switches, opening and closing in response to changes in electrical potentials in the cells where they exist. When the ion channel is opened, it allows for the movement of charged ions across a membrane, thus changing the electrical and chemical properties of the cell. This paradigm for electro-chemical coupling has been used with great success to explain hundreds of observed phenomena. However, there exist a number of physiological events which have been shown to be sensitive to changes in voltage across cell membranes, but which lack the involvement of any known ion channel. This suggests the involvement of other classes of voltage-sensitive proteins.

 

In the last ten years, one such class of proteins has been discovered. The family of voltage-sensitive phosphatases, or VSPs, comprises proteins that contain a voltage-sensor domain very similar to the one found in voltage-gated ion channels. However while the voltage sensor regulates opening and closing of the ion-conducting pore in channels, in VSPs the voltage sensor regulates the activity of a phosphatase. The VSPs in sea squirt and zebrafish are the most well-studied so far, and have been shown to have increased phosphatase activity against the substrate phosphatidylinositol 4,5-bisphosphate (PIP2) in response to depolarization. Experiments utilizing the activity of these proteins have offered important insights into the role of PIP2 in regulating the function of other proteins.

 

Despite the important discoveries made using VSPs as research tools, the normal physiological role of VSPs in cells, and even in which cells VSPs are normally expressed, remains a relatively unexplored field of study. I have found that the VSP from mouse, Mm-VSP, is present in neurons, where its expression levels are regulated throughout development. Furthermore, both the phosphatase domain and voltage-sensing domain of Mm-VSP are functional, suggesting that Mm-VSP plays a role in electrical signaling pathways in neurons (Rosasco et al., Biophys J 2015).

Shown is a movie created in Chimera using the Ci-VSP PDB structures 3V0D, 3V0F, 4G7V, and 4G80. The catalytic domain structures (pink) were reported by Liu et al. in 2011, and the voltage sensing domain structures (blue) were reported by Li et al. in 2014. Since both the voltage sensor and the catalytic domain have crystal structures in the "up/open/on" and the "down/closed/off" states, we can generate a morph between the two states to see what movement of VSPs might look like in cells. The red residues show the arginines, important for sensing voltage across the cell membrane. The blue residue shows a glutamate, proposed to act as a "switch" that regulates access to the catalytic cysteine (shown in orange). The region bridging the voltage sensor and the catalytic domain is not well-resolved. For this video, a part of that linker region was modeled using the CPHmodels 3.2 server (shown in grey).

 

Check out the wikipedia page on VSPs.

 

Transient Receptor Potential Ion Channels (TRPs)

 

How do you sense temperature? Why is it that many types of pain "burn" even though they don't increase your temperature? What makes chili peppers "hot," and what does that have to do with temperature? One reason that we interpret these events similarly, as a "burning" feeling, is that the same ion channels - TRPs - are activated by these diverse stimuli. Thus, in many ways, the electrical signal that your body produces is similar when you eat a jalapeno as when you burn your mouth on a hot slice of pizza. Understanding how TRPs manage to respond to so many diverse stimuli has important implications in developing better treatments for pain, and it is this question that I am currently investigating from a biophysical perspective.

We are experiencing an exciting time in the progression of science and technology. Most of us walk around every day with access to the sum of human knowledge available through devices we keep in our pockets. Successful advancements in data presentation, science communication, and science policy will necessarily take advantage of these new ways of presenting and accessing our ideas.

 

My interests are two-fold. In the "wet lab," I'm absolutely fascinated by the fact that our body runs much like a computer, with a series of intricate circuits operated by electrical switches. I'm particularly interested in the fact that decades after the initial discoveries indicating that our body is an electrical machine, we're still discovering completely new components of this machine. Feel free to browse the "RESEARCH" section of this website for a more in-depth look at some of my work in this field.

 

In front of the computer, I'm interested in new and interesting ways of interacting with data. From the very practical analysis of scientific data sets, to reinterpreting public information in graphically interesting ways, I enjoy exploring the power that modern computing lends to these tasks. In the "FUN" section of this site, you can browse some of my projects exploring different ways of playing with digital data.

 

Alphabubble, Linebounce, Spirograph, and Fading Boxes are all microprojects that I used to explore the lightweight, versatile vector graphics library Raphael.js. Fading boxes was an experiment in continually-looping animation, whereas Alphabubble and Linebounce respond to keyboard input. Spirograph is a customizable recreation of the classic child's toy.

 

Time in Place is a collaborative effort between myself and Loren Judah, where traffic camera data is collected and processed using a Python daemon, and turned into an interactive data visualization using HTML5, Javascript, and the Paper.js library.

 

 

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timeinplace

alphabubble

linebounce

spirograph

 

fading boxes