GENERAL ANESTHETIC RELATED GENES IN DROSOPHILA

General anesthetics have been used clinically for more than one and half century. However, to date, the molecular mechanisms of various anesthetics are not well understood. The state of anesthesia is standardized by the minimum alveolar concentration (MAC) or EC_50 using immobility as an endpoint. The MAC of diethylether, 1.92% atmosphere (atm), in human is similar to the EC_50S for diethylether, 1.94% atm (female) and 1.91% atm (male) of a wild type in Drosophila. We screened mutants found to be hypersensitive and resistant to anesthetics from mutagenized flies by transposon tagging of the P-element and cloned the genes from three ether-sensitive mutants (pard^hd838 ,.eth^as 311 and eth^as 307). The mutation of the sodium channel alpha-subunit is identified in pard^hd838 . Many mutations in the para locus have been isolated by heat-induced paralysis and showed hypersensitivity to diethylether. Although both heat paralysis and anedthesia mechanisms have not yet been clarified, it seems that the two mechanisms are not identical based on our results. The most possible explanation is that diethylether and heat are affected by different repertoires of sodium channel molecules in CNS, since at least 48 different transcripts are expected in the para locus. In eth^as 311, mutation of calreticulin gene is noted, and which shows homology to mammalian calreticulin as a multifunctional Ca^2+ -binding protein in the lumen of the endoplasmic reticulum. Low expression of the gene is found in the mutant. How to induce hypersensitivity to diethylether anesthesia by the reducing? One possible explanation can be formulated from some evidences; that is, diethylether reacts with calreticulin to reduce cell adhesion, stop cell movement and induce a state of anesthesia. eth^as 307 carries a mutation in a gene homologous to a chaperonin eta-subunit. The cct-eta gene is one of eight different subunits of the chaperonin, which is a molecular chaperone and assists in the folding of cytoskeleton proteins such as tubulin and actin. We have to identify the genes of over 20 Drosophila anesthetic mutations, to identify their function and determine their structure and to construct a model of anesthetic action in the near future.