Understanding How Anaesthetics Work In The Brain
An important clue to how anaesthetics work on the human body has been provided by the discovery of a molecular feature common to both the human brain and the great pond snail nervous system, scientists now report. Researchers hope that the discovery of what makes a particular protein in the brain sensitive to anaesthetics could lead to the development of new anaesthetics with fewer side effects.
The scientists hope that their discovery will pave the way for new more targeted anaesthetics with fewer side effects such as nausea. (Credit: Image courtesy of Imperial College London)
The study focuses on a particular protein found in neurons in the brain, known as a potassium channel, which stabilises and regulates the voltage across the membrane of the neuron. Communication between the millions of neurons in the brain — which is the basis of human consciousness and perception, including perception of pain – involves neurons sending nerve impulses to other neurons.
In order for this to happen, the stabilising action of the potassium channel has to be overcome. Earlier studies on great pond snails by the same team identified that anaesthetics seemed to selectively enhance the regulating action of the potassium channel, preventing the neuron from firing at all — meaning the neuron was effectively anaesthetised.
The new research has identified a specific amino acid in the potassium channel which, when mutated, blocks anaesthetic activation. Lead author, Biophysics Professor Nick Franks from Imperial College London, explains how this will allow the importance of the potassium channel in anaesthetic action to be established:
“We’ve known for over 20 years now that these potassium channels in the human brain may be important anaesthetic targets. However, until now, we’ve had no direct way to test this idea. Because a single mutation can block the effects of anaesthetics on this potassium channel without affecting it in any other way, it could be introduced into mice to see if they also become insensitive to anaesthetics. If they do, then this establishes the channel as a key target.”
The group carried out their new study, published in the 20 July issue of the Journal of Biological Chemistry, by cloning the potassium channel from a great pond snail and then making a series of chimeric channels — part snail and part human. The chimeras were used to identify the location of the precise amino acid to which the anaesthetic binds on the potassium channel, giving the team a clearer picture than ever before of the precise mechanism by which anaesthetics work.
This kind of research, explains Professor Franks, is important because understanding exactly how anaesthetics work may pave the way for the development of a new generation of anaesthetics which solely affect specific anaesthetic targets, which could potentially reduce the risks and side effects associated with current anaesthetics.
“At the moment, anaesthetics have many unwanted side-effects on the human body such as nausea and effects on the heart. This is because our current drugs are relatively non-selective and bind to several different targets in the body. A better understanding of how anaesthetics exert their desirable effects could lead to much more specific, targeted alternatives being developed, which could greatly reduce these problems,” he said.
J Biol Chem. 2007 Jul 20;282(29):20977-90. Epub 2007 Jun 4.
Determinants of the Anesthetic Sensitivity of Two-pore Domain Acid-sensitive Potassium Channels: MOLECULAR CLONING OF AN ANESTHETIC-ACTIVATED POTASSIUM CHANNEL FROM LYMNAEA STAGNALIS.
Andres-Enguix I, Caley A, Yustos R, Schumacher MA, Spanu PD, Dickinson R, Maze M, Franks NP.
Biophysics Section, Blackett Laboratory, and Division of Biology, Imperial College, South Kensington, London SW7 2AZ.
Certain two-pore domain K(+) channels are plausible targets for volatile general anesthetics, yet little is known at the molecular level about how these simple agents cause channel activation. The first anesthetic-activated K(+) current I(K(An)) that was characterized was discovered in the mollusk Lymnaea stagnalis and is remarkable for both its sensitivity to general anesthetics and its stereoselective responses to anesthetic enantiomers (Franks, N. P., and Lieb, W. R. (1988) Nature 333, 662-664 and Franks, N. P., and Lieb, W. R. (1991) Science 254, 427-430). Here we report the molecular cloning of a two-pore domain K(+) channel LyTASK from L. stagnalis and show that, when expressed in HEK-293 cells, it displays the same biophysical characteristics as the anesthetic-activated K(+) current I(K(An)). Sequence analysis and functional properties show it to be a member of the TASK family of channels with approximately 47% identity at the amino acid level when compared with human TASK-1 and TASK-3. By using chimeric channel constructs and site-directed mutagenesis we have identified the specific amino acid 159 to be a critical determinant of anesthetic sensitivity, which, when mutated to alanine, essentially eliminates anesthetic activation in the human channels and greatly reduces activation in LyTASK. The L159A mutation in LyTASK disrupts the stereoselective response to isoflurane while having no effect on the pH sensitivity of the channel, suggesting this critical amino acid may form part of an anesthetic binding site.
PMID: 17548360 [PubMed – in process]