 Going under the knife? Whether it's to have your appendix removed or a triple bypass, you'll need anesthesia. The powerful drugs temporarily render you unconscious, and eliminate any awareness of sensation, including pain, to make surgery possible. Scientists know a lot about how these chemicals work, but there are still mysteries about what happens at the molecular level. Where exactly does Propofal bind to produce its body and mind-numbing magic? What about barbiturates? Now, a team at Massachusetts General Hospital has studied four anesthetics in detail, revealing differences and similarities in how they work. Many general anesthetics work in part by boosting the activity of inhibitory receptors in the brain and spinal cord. These receptors are tiny channels that respond to the neurotransmitter GABA. When GABA binds, the channels open up and allow chloride ions to flow in, making it harder for neurons to activate. Brain activity and results in sedation and, ultimately, unconsciousness. But each anesthetic binds to different parts of the GABA receptor and achieves its calming effect a little differently. To map the precise points of contact, the Mass General researchers used two separate genetic techniques to modify the structure of the GABA receptors. The scientists selected six amino acids for testing. These were located in pockets between the five subunits that surround the central pore. In one set of experiments, the researchers changed these residues to bulky tryptophanes. At some locations, such as between the alpha and beta subunits, mutations reduced the ability of the anesthetic to enhance the receptor's response to GABA, suggesting the drugs normally occupy these sites. In a second set of experiments, scientists replaced the amino acids with cysteines that would be modified by a reagent unless the site was bound or protected by the anesthetic. Thus, the degree of cysteine protection provides a proxy for anesthetic contact. This method was compared with another technique called photolabeling, in which a light-activated anesthetic molecule sticks to the receptor near the drug binding site. The cysteine method was remarkably consistent with previous photolabeling experiments, indicating it is a reliable technique. It also identified new points of contact. In the end, the researchers found that the general anesthesia drug atomidate binds to the GABA receptor between the alpha and beta subunits, whereas a barbiturate binds between the alpha and beta or gamma and beta subunits. Propofol binds near, but not exactly on, all of these sites. On the other hand, a neuroactive steroid didn't bind to any of these locations, and none of the drugs made contact between the alpha and gamma subunits. The remarkable finding is that these anesthetics, all of which produce sedation and unconsciousness, bind to the receptor at different locations. Understanding these sites could be useful in the future and may lead to the development of better anesthetics, giving patients more options and potentially safer surgeries.