Naresh Dhanasekar is a postdoctoral researcher at Western University of Health Sciences. He investigates the cooperative behavior of mechanosensitive Piezo ion channels to uncover fundamental principles of cell signaling and mechanotransduction. In this Postdoc Portrait interview, he shares the importance of his work and what he hopes his research will accomplish.
Deciphering PIEZO Channel Cooperativity in Mechanotransduction
Q | What scientific problem are you trying to solve?
Currently, I am interested in understanding the cooperative behavior of pressure sensitive Piezo channels under in-vitro environment. It is well established that Piezo ion channels are essential mechanosensors which respond to light touch (pressure) and proprioception. It remains unclear whether these channels operate as a single unit or exist as clusters on the membrane.
Addressing this important question is fundamental to understanding how cells achieve both high sensitivity and robustness when responding to mechanical stimuli. By identifying the key mechanism which contributes to the cooperative channel behavior I aim to uncover the principles governing the mechanotransduction behavior of these ion channels across diverse cell types. Furthermore, understanding channel cooperativity could also open new avenues for designing new therapeutic targets for disorders associated with mechanotransductive behavior such as cardiovascular, gastrointestinal and cancer.
Q | What drew you to studying single-molecule electrophysiology?
My interest in single-molecule electrophysiology began during my graduate studies in Germany, where I became fascinated by how bacterial membrane protein channels generate electrical signals when they interact with antibiotics or sugar molecules in a simple yet powerful in vitro system. I was struck by the remarkable selectivity of these nanoscale protein pores—typically only 1nm in diameter—which can precisely discriminate between molecules, while other channels can transport much larger molecules measuring several kilodaltons. Studying how such small molecular machines produce highly specific electrical responses sparked my fascination with ion channel biophysics.
That curiosity naturally led me to my current postdoctoral research, where I investigate mechanosensitive Piezo ion channels using patch-clamp electrophysiology. What draws me most to this field is the ability to convert mechanical stimuli such as pressure and light to be converted into electrical signals that control fundamental physiological processes. I am particularly intrigued by the observation that these electrical responses differ dramatically between single-channel and multichannel environments, even when the same mechanical force is applied. Understanding the mechanisms underlying this behavior motivates my research into PIEZO channel cooperativity.
Q | What’s one thing you learned from your research that you didn’t expect?
One important aspect which I now understand about these mechanosensitive Piezo channels is that the complete physiological behavior of these channels cannot be understood by studying under isolated conditions. I initially expected that the activity of multiple Piezo ion channels would arise from the sum of individual channel behavior. Instead, I found that the electrical signals generated by these channels in a multichannel environment can differ substantially from those of single channels, even when the same kind of mechanical stimulus is applied. This observation challenged my assumptions and led me to investigate the possibility that neighboring Piezo channels interact cooperatively through their shared membrane environment. This experience from Piezo has led me to understand that complex cellular behaviors often emerge from interactions between proteins rather than from individual proteins alone.
Biophysical Mechanisms and Potential Therapeutic Targets
Q | If your research succeeds, what could it change for science or society?
Although Piezo ion channels are known to play essential roles in touch, proprioception, vascular biology, and many other physiological processes, it remains unclear how these channels behave under cooperative environments. By uncovering the channel cooperative behavior, my work would provide new insights into mechanotransduction that extends beyond a single cell. In future, this could have important implications for human health. For instance, dysfunction of Piezo channels has been linked to disorders including cardiovascular diseases, blood disorders, and recently reproductive biology. A better understanding of how these channels function in a cooperative environment would offer new therapeutic strategies for targeting signaling pathways. I certainly believe that my research on Piezo contributes to the growing field of mechanobiology, providing additional insights into how physical forces shape cellular behavior in both normal and pathological conditions.
Q | What question are you most excited to answer next?
I now have a clear hint that from our simulations and single-molecule imaging experiments that these Piezo channels exist in clusters. My next question in these processes is: What controls this clustering or cooperative behavior in the membrane. For instance, does the lipid membrane itself determine how neighboring channels interact? Can changes in the cytoskeleton influence cooperative behavior and hence the mechanotransduction process? Is this cooperative behavior conserved across different cell types? Answering these complex questions would shed more light on how cells convert physical forces into biological signals. More importantly, these would help us in designing new therapeutic drugs that could potentially solve the disorders related to Piezo ion channels.
Responses have been edited for length and clarity.
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