Author: Liebers Kate
Date: December 2007
Evolution has been very conservative. For example, it is hard to believe how closely our nervous system resembles that of marine snails, tiny slimy creatures. The marine snail, has approximately 20,000 neurons in its central nervous system; humans have approximately one trillion. The large brain cells of this animal make it easy to study the effects of one cell in relation to another. Taking advantage of this simplicity and similarity at the cellular level, scientists have relied on the snail as a model to learn about anesthetics.
A big problem with anesthetics currently is that they have many unwanted side-effects on the human body such as nausea and effects on the heart. This is due to the non-selectivity of the drugs causing them to bind to several targets in the body. Identifying the specific amino acids to which these anesthetics bind could reatly reduce our problems, said Nick Franks, a professor of biophysics and anesthetics.
A review of the nervous system
Nerve cells (neurons) present in our nervous system communicate with each other in response to stimuli helping us to perceive sensations such as sound, light and pain. The potassium channel plays a significant regulation role in this communication process.
The channels are proteins structured of amino acids. Current anesthetics work by numbing the nerve pathways in potassium channels, preventing certain stimulus from being received as pain.
Yet this process is fairly non-exclusive; whole proteins are understood to be the binding targets of anesthetics. Whether the effects of the drugs are due to a relatively small number of molecules sites or the combined effects of many molecular sites has remained a mystery that the researchers from Imperial College sought to resolve.
That's where the great pond snail, Lymnaea stagnalis, comes in.
According to the report published June 4, 2007 in The Journal of Biological Chemistry, this mollusk is exceptionally sensitive to general anesthetics and a series of tests (including RNA sequence analyses and examinations of functions) have shown that its potassium channels share almost half of the same amino acids found in human nervous system channels. Conveniently, the contrast between snail and human is that snail proteins are four to five times more sensitive than those of humans, making it easy for researchers to analyze affects of anesthetics upon altering certain portions of the potassium channel.
The scientists first contruced a part-snail, part-human chimeric channel and introduced mutations to specific sites on the constructs. This exposed a single determining amino acid of anesthetic response; it was the amino acid that, when mutated, eliminated the effects of anesthetics in the human channels.
This discovery that a single amino acid (not a series of sites or a group in the form of a protein) is largely responsible for anesthetic response is a significant step in solving the mystery regarding the exact process by which this commonly administered medical drug functions. The implications of this research hold promise for those who receive anesthetics, since drugs that can target fewer parts of the body while retaining their effectiveness would most likely result in few side effects, such as nausea in terms of anesthetics.
Although much anesthetics research suggests the influence of the pain-numbing process on amino acids, Franks said the trick was to devise a method to find which of these amino acids were affected. The currently established process involves extracting RNA from the snail, analysis of the nucleotide sequences, cloning cells, site-directed mutations, constructing snail-human cell hybrids, extracting certain areas of the cell constructs and administering anesthetic solutions.
Further study can be conducted using mice test subjects that are genetically engineered to have the specific mutation preventing response to anesthetic drugs.
"If the mouse is also insensitive to anesthetics," Franks stated, "then this [would show] that the anesthetic sensitive potassium channel is an important target in a mammal."
Although this research going in the direction of finding answers to more effective anesthetics, Franks speculated that it would be many years before such work could lead to new and improved versions of the pain inhibitors.
Written by Kate Liebers
Reviewed by Gurjot Singh, Pooja Ghatalia
Published by Pooja Ghatalia.