Molecular and Cellular Mechanisms of Mechanotransduction

Every organ, tissue and cell of the human body is constantly exposed to mechanical forces. Life evolved mechanisms to detect these mechanical forces and translate them into electrical or chemical signals. This process is called mechanotransduction and enables organs, tissues and cells to adequately respond.

The Grandl Lab particularly focuses on rapid mechanotransduction, which is initiated within less than one millisecond and enabled by force-gated ion channels. In order to capture such fast processes we routinely use immortalized cell-lines to express our ion channels of interest and patch-clamp electrophysiology to measure their activity with sub-millisecond precision. A particular strength of our lab is the development of novel biophysical approaches to investigate and ultimately understand mechanotransduction.

Our research contributes to understanding fundamental biology, such as the sense of light touch, and human disease, such as inflammatory pain, chronic pain, and itch. As a consequence the results of our work are of broad interest for the development of treatments of disease.

Two fundamental questions drive our work:

1) How do force-gated ion channels work?

We want to understand how mechanical energy gates (activates, inactivates and deactivates) ion channels and how compromising specific aspects of gating leads to human diseases.

2) How are cells sensing mechanical energy?

We aim to explain how many individual force-gated ion channels function in concert and give rise to complex mechanotransduction in living cells.

For those new to the field, our recent review provides an introduction: Touch, Tension, and Transduction - The Function and Regulation of Piezo Ion Channels.

1. Michael N Young, Michael J Sindoni, Amanda H Lewis, Stefan Zauscher, and Jörg Grandl. The energetics of rapid cellular mechanotransduction. PNAS (2023).

   ---

2. Amanda Lewis and Jörg Grandl. Piezo1 ion channels inherently function as independent mechanotransducers. eLife (2021).

   ---

3. Amanda Lewis and Jörg Grandl. Inactivation Kinetics and Mechanical Gating of Piezo1 Ion Channels Depend on Subdomains within the Cap, Cell Reports (2020).

   ---

4. Jason Wu, Michael Young, Amanda H. Lewis, Ashley N. Martfeld, Breanna Kalmeta and Jörg Grandl. Inactivation of Mechanically Activated Piezo1 Ion Channels is Determined by the C-Terminal Extracellular Domain and the Inner Pore Helix, Cell Reports (2017).

5. ---

   Amanda Lewis, Alisa Cui, Malcolm McDonald and Jörg Grandl. Transduction of repetitive mechanical stimuli by Piezo ion channels, Cell Reports (2017).

   ---

6. Wu, J. et al. Localized force application reveals mechanically sensitive domains of Piezo1. Nature. Communications. 7, 12939 doi: 10.1038/ncomms12939 (2016).

7. ---

   Amanda Lewis and Jörg Grandl. Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension, eLife (2015).

8. ---

   Sairam Jabba, Raman Goyal, Jason Sosa-Pagan, Hans Moldenhauer, Jason Wu, Breanna Kalmeta, Michael Bandell, Ramon Latorre, Ardem Patapoutian and Jörg Grandl. Directionality of temperature-activation in mouse TRPA1 ion channel can be inverted by single-point mutations in ankyrin repeat six. Neuron (2014).

9. ---

   Bertrand Coste, Bailong Xiao, Jose S. Santos, Ruhma Syeda, Jörg Grandl, Kathryn S. Spencer, Sung Eun Kim, Manuela Schmidt, Jayanti Mathur, Adrienne E. Dubin, Mauricio Montal and Ardem Patapoutian. Piezos are pore-forming subunits of mechanically activated channels. Nature, 483 (7388), 176-181 (2012).

10. ---

    Jörg Grandl, Sung Eun Kim, Valerie Uzzell, Badry Bursulaya, Matt Petrus, Michael Bandell and Ardem Patapoutian. Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain. Nature Neuroscience, 13 (6), 708-14 (2010).

11. ---

    Jörg Grandl, Hongzhen Hu, Michael Bandell, Badry Bursulaya, Manuela Schmidt, Matt Petrus and Ardem Patapoutian. Pore region of TRPV3 ion channel is specifically required for heat activation. Nature Neuroscience, 11 (9), 1007-13 (2008).

1. Measuring the Lightest Touch Your Body Responds To  - Pratt News

   ---

2. Finally Getting to Scratch That Itch - Pain Research Forum

   ---

3. Sensing the pressure - eLife

   ---

4. Mole-Rat Pain Resistance Could Point the Way to New Analgesics - Scientific American

   ---

5. When Touch Causes Itch: A New Role for Merkel Cells in the Skin - Pain Research Forum

   ---

6. A cellular mechanism for age-induced itch - Science

   ---

7. Piezo2 Comes in More Forms than One - Pain Research Forum

   ---

8. Proteins get touchy under pressure - Chemistry World - The Royal Society of Chemistry

   ---

9. Why do we feel hot and cold as pain? - BBC Future

   ---

10. Getting in Touch with Jörg Grandl -Trends in Biochemical Science (TIBS)

    ---

11. A Tour De (Tiny) Force - Duke Today

    ---

12. Turning Duke Experiences into Science Fair Gold - Duke Research Blog

    ---

13. Pain-Sensing Gene Named for Rocky - Duke Today

Alisa Cui 
Yale University

Raman Goyal
UC Davis

Ann Huynh

Sairam Jabba
Duke University

Breanna Kalmeta

Malcolm MacDonald
MD Anderson Cancer Center

Ashley Martfeld  
Cato Research

Arathi Ponugoti
Duke University

Jason Sosa-Pagan

Lea Wittman
Würzburg University

Jason Wu
Harvard University

We have openings for postdoctoral fellows, graduate students and Duke undergraduate students with interest in ion channel research. To apply to the lab, send cover letter, CV and contact details of 2-3 references as a single PDF file to Jorg Grandl: grandl@neuro.duke.edu.