The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonistmediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, sitedirected mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride.
Background
Anesthetic gases have been known to cause damage when inhaled over long periods of time. Modern safety measures have been put in place to reduce the risk to anesthesia providers, however there is continued lack of information on providers experiencing short term effects (lethargy, fatigue, headache, slowed cognitive ability, nausea, and mucosal irritation) thereby leading to long-term sequalae (sister chromatid exchanges, micronuclei, chromosomal aberrations, and comet assays).
Method
A thirteen item, multiple choice survey was sent to 3,000 anesthesia providers, of which 463 completed the survey. A Chi-square test of independence was used to determine the association between gas exposure and participant self-reported symptoms. A Spearman’s Correlation test was also utilized to interpret this data since both frequency of smelling gas and frequency of symptoms were ordinal variables for which Spearman’s rho correlation was the appropriate measure of association.
Results
The major findings were that as the frequency of smelling anesthetic gas increased, so too did the frequency of self-reported headaches and fatigue. Spearman’s rho = .148 and .092. P value = .002 and .049, respectively.
Conclusion
There have been many efforts to decrease the risk of exposure of anesthesia providers to anesthetic gases. While there is a decrease in reported exposures, indications of possible long-term effects remain a concern in anesthesia providers. Potential implications of exposure could lead to chromosomal aberrations, sister chromatid exchanges, comet assays, spontaneous abortions, and genotoxic effects.
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