Kriston Jae Bethel/The New York Times

Pore dilation leads to a greater influx and outflux of particles, which can increase particle transmission if there is an uneven concentration inside or outside the cell.

October 18, 2023

New Ion Channel Study Could Impact How Drugs Are Administered

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A new understanding of how drugs are taken in by cells could impact the way drugs are administered to patients. In an Aug. 30 study published in Nature that details structural changes of the Transient Receptor Potential Vanilloid ion channel family when overexposed to activating compounds, Weill Cornell researchers Shifra Lansky, Simon Scheuring and Crina Nimigean, Ph.D. tracked the structure of these channels as pore enlargement was induced.

TRPV is a classification of Transient Receptor Potential ion channels that responds to natural molecules in compounds, such as spicy foods. This ion channel is also involved in the regulation and measurement of internal body temperature and external environment temperature sensation.

For example, the heat felt after eating a spicy meal is due to capsaicin — an active component of chili peppers — binding to the TRP1 receptor. When capsaicin binds to TRP1, it activates the heat sensor, causing an increase in body temperature and heat sensation. 

In the TRPV ion channel family, the temperature sensors and compound receptors have been scientifically recognized as tetrameric, meaning they are made up of four subunits with a pore in the middle to stimulate movement of ions through the outer layer of the cell. 

Nimigean’s lab focuses on the relationship between ion channel structure and their mechanisms within biological processes and systems, such as the TRP channels, which were believed to be tetramers until her lab discovered the five unit, pentameric characteristic. 

Using techniques like atomic force microscopy, live images were taken of TRPV channels forming a star shape by incorporating another subunit into their structure. This meant that the ion channel was adopting a new conformation through an external method — not an internal change. 

Atomic force microscopy works like a record player — it uses a very small tip to scan the protein’s surface, which creates a topography map of the molecules, providing a detailed image of the bumps and ridges of the surface of ion channels. Atomic force microscopy allows for this analysis through high speed image acquisition due to its ability to capture multiple frames per second. 

“The biggest advantage of the massive diversity is that this TRP doesn’t care if it is in air or in liquid, you can actually watch the molecules in a native environment and have the molecules perform their native function while you watch them,” Scheuring said.  

In the images captured through this type of microscopy, Schering and Nimigean discovered the fifth subunit that transformed into a star-like shape.  

The change in structure is likely in response to its environment due to prolonged exposure to the addition of activating compounds, causing the middle pore to enlarge. 

This phenomenon, known as pore dilation, leads to a greater influx and outflux of particles, which can increase particle transmission if there is an uneven concentration inside or outside the cell. Ion channels are meant to maintain the gradient of particles inside and outside the cell, so pore dilation could be a response to an unequal distribution in both sides. 

To confirm whether the pentameric transition was pore dilation, Scheuring added a compound called DPPA, which is a stimulant that induces pore dilation within the ion channels. 

They found that when pore dilation was induced, the number of pentameric ion channels increased, meaning that this prolonged activation of the ion channels may lead to the structural change. 

Although it is not yet well understood why these structural changes occur in the body, one hypothesis states that it may be a response to disease mutations that cause unstable protein interfaces.  

There are many topics that are currently being explored such as how pore dilation is being used to more effectively get medication into the cell. These discoveries have great implications for medical understanding and can lead to more targeted drug therapies for debilitating diseases. 

“The population has already used this phenomenon to deliver drugs without knowing how it works,” Scheuring said. “Because, often, it is a problem to bring a drug into a cell.” 

Another avenue of exploration is the way that these structural changes may be involved in genetic diseases. 

“It could be that these disease mutations make this interface more or less stable and the tetramer would fall apart much more easily,” Scheuring said. “And then obviously, as a consequence, you could imagine that if the tetramer falls apart more easily, it could create new pentacles. These disease mutations are certainly also something we want to investigate.”

Cristina Torres can be reached at [email protected].