| Introduction. Volatile anesthetics have been in widespread use for over 150 years. The correlation of potency of volatile anesthetics and with lipid solubility has led to the formation of a unitary hypothesis, that all volatile anesthetics work via the same mechanism. However, due to the physical characteristics of volatile anesthetics and the complicated behavioral phenotype of anesthesia, it has not been possible to identify either a target or mechanism of action for these drugs. We have taken a pharmacogenetic approach to this problem, studying mutants of C. elegans with altered anesthetic sensitivities. One particular mutant, unc-79, has increased sensitivity to some volatile anesthetics but resistance to others. The pattern of anesthetic sensitivity of unc-79 is inconsistent with the unitary hypothesis.; Results. The unc-79 gene was localized to a 17 kb region of chromosome III. The gene was determined to consist of 27 exons in a 6.4 kb mRNA which codes for a predicted protein of 2084 amino acids. Six of six alleles of unc-79 have significant mutations present in this mRNA. Like C. elegans only one unc-79 -related gene is present in Drosophila, rodents and humans. UNC-79 is expressed in the nervous system of all four organisms. An antibody raised to the UNC-79 protein identified a C. elegans protein of about the expected size, 235 kDa. Fractionation experiments indicate that this protein is found predominately in the fractions corresponding to Golgi or extracellular matrix. Double mutants for unc-79 and the PI(3)P kinase age-1 were synthetic lethals. An unc-79 Northern reveals only a single band almost twice the size of the mature mRNA. This large transcript is more prevalent than the mature mRNA and retains several introns consistent with a partially spliced form of the message.; Discussion. UNC-79 is the first identified member of a novel family of proteins expressed in the nervous systems of organisms as varied as nematodes, fruit flies and humans. Expression of the gene is probably regulated, at least in part, by stringent control of splicing. The interaction of unc-79 with a phosphotidylinositol kinase indicates that UNC-79 may function in this pathway to modulate responses to volatile anesthetics. |
