A genetic study of the anesthetic response: Mutants of Drosophila melanogaster altered in sensitivity to halothane

Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD 20892.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/1990; 87(21):8632-6. DOI: 10.1073/pnas.87.21.8632
Source: PubMed


In an attempt to identify genes that control or encode the targets of general anesthetics, we have chemically mutagenized fruit flies and selected four lines that show an abnormal response to the volatile anesthetic halothane. Specifically, about 2-fold higher concentrations of halothane are required to induce the loss of motor control in the mutant flies. Fine mapping of two isolates indicates that they alter a previously uncharacterized gene of Drosophila. In the absence of anesthetics, these mutants display alterations of behavior that imply changes in the adult and the larval neuromuscular system.

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Available from: KS Krishnan
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    • "They are also more resistant to flurothyl and enflurane, insensitive to fluroxene and isoflurane, and mildly more sensitive to diethylether (Morgan and Cascorbi, 1985; Morgan et al., 1988, 1990; Humphrey et al., 2007). By contrast, hypomorphic nahar38 and nahar85 drosophila mutants were first described as resistant to halothane, methoxyflurane, chloroform and trichloroethylene but not to diethylether, isoflurane, and enflurane (Krishnan and Nash, 1990; Nash et al., 1991; Campbell and Nash, 1994; Mir et al., 1997). However, it was then reported that unc-79 and na mutants are hypersensitive to halothane but not enflurane (Guan et al., 2000; Humphrey et al., 2007). "
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    ABSTRACT: Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs). There is growing evidence that the NALCN channelosome critically regulates its ion conduction. Both in mammals and invertebrates, animal models revealed an involvement in many processes such as locomotor behaviors, sensitivity to volatile anesthetics, and respiratory rhythms. There is also evidence that alteration in this NALCN channelosome can cause a wide variety of diseases. Indeed, mutations in the NALCN gene were identified in Infantile Neuroaxonal Dystrophy (INAD) patients, as well as in patients with an Autosomal Recessive Syndrome with severe hypotonia, speech impairment, and cognitive delay. Deletions in NALCN gene were also reported in diseases such as 13q syndrome. In addition, genes encoding NALCN, NLF- 1, UNC-79, and UNC-80 proteins may be susceptibility loci for several diseases including bipolar disorder, schizophrenia, Alzheimer's disease, autism, epilepsy, alcoholism, cardiac diseases and cancer. Although the physiological role of the NALCN channelosome is poorly understood, its involvement in human diseases should foster interest for drug development in the near future. Toward this goal, we review here the current knowledge on the NALCN channelosome in physiology and diseases.
    Full-text · Article · May 2014 · Frontiers in Cellular Neuroscience
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    • "In flies, volatile organic solvent anesthetics, such as halothane and isoflurane, induce a state of sedation characterized by complete immobility and the loss of the ability to maintain postural control or respond to stimuli (Allada and Nash, 1993; Krishnan and Nash, 1990). Less-volatile organic solvents, such as ethanol and benzyl alcohol, have been shown to induce a biphasic response characterized by a brief initial increase in locomotor activity followed by sedation (Cowmeadow et al., 2005; Ghezzi et al., 2004; Moore et al., 1998; Parr et al., 2001; Scholz et al., 2000). "
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    ABSTRACT: Drug addiction is a complex condition of compulsive drug use that results in devastating physical and social consequences. Drosophila melanogaster has recently emerged as a valuable genetic model for investigating the mechanisms of addiction. Drug tolerance is a measurable endophenotype of addiction that can be easily generated and detected in animal models. The counteradaptive theory for drug dependence postulates that the homeostatic adaptations that produce drug tolerance become counteradaptive after drug clearance, resulting in symptoms of dependence. In flies, a single sedation with ethanol or with an organic solvent anesthetic (benzyl alcohol) induces functional tolerance, an adaptation of the nervous system that reduces the effect of these neural depressants. Here we review the role of the BK channel gene (slo) and genes that encode other synaptic proteins in the process of producing functional tolerance. These proteins are predicted to be part of an orchestrated response that involves specific interactions across a highly complex synaptic protein network. The response of the slo gene to drug exposure and the consequence of induced slo expression fit nicely the tenets of the counteradaptive theory for drug tolerance and dependence. Induction of slo expression represents an adaptive process that generates tolerance because it enhances neuronal excitability, which counters the sedative effects of the drugs. After drug clearance, however, the increase in slo expression leads to an allostatic withdrawal state that is characterized by an increase in the susceptibility for seizure. Together, these results demonstrate a common origin for development of drug tolerance and withdrawal hyperexcitability in Drosophila.
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    • "In addition to the defect in behavioral circadian rhythms, the Drosophila mutant also displays other phenotypes, including narrow abdomen and altered sensitivity to anesthetics (Krishnan and Nash, 1990; Mir et al., 1997; van Swinderen, 2006). The complexity of the phenotypes suggests additional physiological roles of the NALCN channel. "
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    ABSTRACT: Sodium plays a key role in determining the basal excitability of the nervous systems through the resting "leak" Na(+) permeabilities, but the molecular identities of the TTX- and Cs(+)-resistant Na(+) leak conductance are totally unknown. Here we show that this conductance is formed by the protein NALCN, a substantially uncharacterized member of the sodium/calcium channel family. Unlike any of the other 20 family members, NALCN forms a voltage-independent, nonselective cation channel. NALCN mutant mice have a severely disrupted respiratory rhythm and die within 24 hours of birth. Brain stem-spinal cord recordings reveal reduced neuronal firing. The TTX- and Cs(+)-resistant background Na(+) leak current is absent in the mutant hippocampal neurons. The resting membrane potentials of the mutant neurons are relatively insensitive to changes in extracellular Na(+) concentration. Thus, NALCN, a nonselective cation channel, forms the background Na(+) leak conductance and controls neuronal excitability.
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