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Better understanding of voltage-gated-like ion channels may spark improvements in general anesthesia

by Susan Szuch

Up until recently, there has been very little understanding on how exactly general anesthesia worked. Vincenzo Carnevale, Research Associate Professor at Temple University in Pennsylvania, is part of a team of researchers who is trying to do just that by understanding the functional mechanisms of voltage-gated-like ion channels.

“We do know that a certain set of molecules are able to induce reversible loss of consciousness, analgesia, amnesia and immobility, the hallmarks of the medically induced state of general anesthesia,” Carnevale says. “But we don’t know much about the molecular mechanisms responsible for this response.”

By finding out the molecular mechanisms, Carnevale is hoping to improve anesthesia.

“Understanding the molecular mechanism of current general anesthesia agents is a prerequisite for designing novel molecules with reduced side effects and increased potency,” Carnevale says.

Carneval and the researchers he has worked with would not be able to do that without the assistance of Blue Waters.

To examine these channels, the team performed extensive molecular dynamics simulations. These were observed over several micro-seconds in membrane protein structures which were typically the size of 300,000 atoms.

The in silico structural model comprised the ion channel, a lipid bilayer, tens of thousands water molecules and hundreds of ions, for a total of several hundred thousand atoms.

The computational capabilities of Blue Waters were crucial for the success of this research.

“We needed to observe the microscopic dynamics of this system for quite a long stretch of time, so that’s why Blue Waters instrumental,” Carnevale says. “We could not have done this without such a powerful computational resource.”

Voltage-gated ion channels enable signal transmission within neurons by generating and propagating the so-called “action potential.” This results from a remarkably concerted action of sodium and potassium channels. A protein module called the “voltage-sensing domain” ensures that channels open at the right time in response to an electrical signal.

The internal structure of the voltage-sensing domain has been deciphered, but the question remains: What is the coupling between the voltage-sensing domain and the pore domain where ions flood in?

“We would like to understand how a movement in one domain affects the state of the other domain, in other words, we want to understand the mechanical properties of this nanoscale molecular machine.” Carnevale says.

In addition to voltage-gated ion channels, Carnevale is trying to understand the functioning of related channels, the TRP channels, which, instead of being activated by electrical signals, are responsive to stimuli like binding of ligands, pH or temperature.

“Once we understood the nature of the mechanical coupling between the voltage sensor and the pore domains in voltage gated ion channels, we asked ourselves: Are structurally similar and evolutionary related channels all characterized by the same mechanical properties? To our surprise we found that TRP channels show a markedly different mechanical coupling between the two domains, suggesting the temperature or pH sensitivity rely on completely different molecular mechanisms.” Carnevale says.

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