P.G. Morgan, MD & M.M. Sedensky
The molecular mechanism of action of volatile anesthetics remains one of the intriguing mysteries of modern medicine. The complexity of the mammalian brain, coupled with ubiquitous effects of volatile anesthetics on subcellular processes, have impeded extensive research efforts aimed at deciphering the modes of action of these compounds. However, volatile anesthetics disrupt fundamental processes of neuronal function that appear highly conserved across many disparate phyla. We reasoned that studies in a simple model system might provide a powerful approach to identifying genes that influence anesthetic sensitivity. Our laboratory exploits a very simple animal model, the nematode C. elegans, to investigate the molecular mechanism of volatile anesthetic action. We established that genes and physiologic pathways that alter anesthetic sensitivity in the nematode also alter sensitivity in other animals. The importance of the fact that the same molecular pathways affect sensitivity across different species is hard to overstate. The genes we have identified code for a group of interacting proteins. The proteins include a novel group of cation channels present in the nervous systems of all animals (NCA-1 and NCA-2), a sodium channel orthologous to the acid sensing ion channels (UNC-8) and proteins which affect their stability and distribution (UNC-79 and UNC-1) As a group, they form novel targets for volatile anesthetics that are of general importance. We hypothesize that 1. NCA-1 and NCA-2 are proteins integral to presynaptic function. 2. UNC-79 directly interacts with NCA-1 and NCA-2. And 3. Volatile anesthetics inhibit NCA-1 and NCA-2 function. The specific aims to test this hypothesis are 1. Characterize the expression and interactions of the NCA proteins. 2. Determine the mechanism by which UNC-79 controls the NCA proteins. 3. Characterize the mechanism by which anesthetics affect the NCA proteins. Our experiments are intended to determine the cellular location and the function of the NCA channels and of UNC-79. In addition, the electrophysiologic studies will characterize the actions of the channels. Finally, we will study the effects of volatile anesthetics on the function of the NCA channels. Our work has shown that these channels and their interacting proteins of general significance in the nervous systems of animals. As a result, understanding how they have such profound effects on anesthetic sensitivity represents a paradigm shift in the efforts to understand how volatile anesthetics function.
PUBLIC HEALTH RELEVANCE: This work is directed at elucidating the mechanism of action of inhaled general anesthetics, one of the mysteries of modern medicine. Understanding how these anesthetics function may contribute to improvements in design of anesthetics and in the understanding of consciousness.