During surgery, deep sedation and analgesia are critical for reducing the trauma of incision. Many anesthetic drugs are used in operating rooms, but it’s still unclear how exactly they work. Researchers from Department of Neuroscience at Jefferson (Philadelphia University + Thomas Jefferson University) and colleagues recently published two papers to help untangle the mystery behind propofol, one of the most commonly used anesthetic agents in sedation and surgery, and a drug whose discovery was recently lauded with a Lasker-DeBakey Clinical Medical Research Award.

The sense of pain transmits harmful signals from the body to the brain. In order to block pain, anesthetic drugs work through multiple mechanisms, one of which is via blocking neural transmission. As computer processes information relying on electric current, our nervous system transmits information through electrical pulses called action potentials.

Neurotransmitters released at nerve terminals trigger the action potential by opening selective ion channels. One of the main ion channels is the sodium channel, a sort of “tunnel” for sodium flow in neuronal membranes. Preventing that sodium flow can block action potentials, and therefore shut down brain signaling in three different ways. Anesthetics work by interacting with the sodium channel by 1) blocking or clogging the opening of the channel, 2) inactivating the channel by twisting the channel protein, or 3) stabilizing the channel’s inactivate state.

Researchers know that local anesthetics, such as lidocaine and benzocaine, act as pore-blockers; it was unknown, however, whether the general anesthetic propofol worked the same way. Using patch-clamp, a technique that can measure microscopic current flow through sodium channels, Elaine Yang, a Sidney Kimmel Medical College MD-PhD student working in the laboratory of Manuel Covarrubias, MD, PhD, professor of neuroscience and researcher at the Vickie and Jack Farber Institute for Neuroscience – Jefferson Health, found that propofol does not work as a pore-blocker. Rather, the drug promotes a type of inactivation that surprisingly strictly depends on sodium channel activation and opening. This seemingly paradoxical result suggested that propofol used multiple binding sites.

To shed light on the molecular mechanism of action, the researchers also investigated where propofol binds to the sodium channel. Using a new technique called STD NMR spectroscopy that can detect low-affinity interactions in membrane proteins, the team identified three binding sites, including extracellular and intracellular pockets that may function differently in channel activation and inactivation. These binding sites provide evidence to support the ‘dual’ role of propofol: different binding combinations enhance either the inactivation and activation roles, but more experiments are needed to explore this idea.

This work by Dr. Covarrubias and colleagues was recently featured in a news feature article in the Journal of General Physiology.?