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Biochim Biophys Acta,
2014]
As biological force-sensing systems mechanosensitive (MS) ion channels present the best example of coupling molecular dynamics of membrane proteins to the mechanics of the surrounding cell membrane. In animal cells MS channels have over the past two decades been very much in focus of mechanotransduction research. In recent years this helped to raise awareness of basic and medical researchers about the role that abnormal MS channels may play in the pathophysiology of diseases, such as cardiac hypertrophy, atrial fibrillation, muscular dystrophy or polycystic kidney disease. To date a large number of MS channels from organisms of diverse phylogenetic origins have been identified at the molecular level; however, the structure of only few of them has been determined. Although their function has extensively been studied in a great variety of cells and tissues by different experimental approaches it is, with exception of bacterial MS channels, very little known about how these channels sense mechanical force and which cellular components may contribute to their function. By focusing on MS channels found in animal cells this article discusses the ways in which the connections between cytoskeleton and ion channels may contribute to mechanosensory transduction in these cells. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve.
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Toxicol Appl Pharmacol,
2002]
A critical element of any experimental design is the selection of the model that will be used to test the hypothesis. As Claude Bernard proposed over 100 years ago "the solution of a physiological or pathological problem often depends solely on the appropriate choice of the animal for the experiment so as to make the result clear and searching." Likewise, the Danish physiologist August Krogh in 1929 wrote that "For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied." This scientific principle has been validated repeatedly in the intervening years as investigators have described unique models that exploit natural differences in chemical and molecular structure, biochemical function, or physiological response between different cells, tissues, and organisms to address specific hypotheses. Despite the power of this comparative approach, investigators have generally been reluctant to utilize nonmammalian or nonclassical experimental models to address questions of human biology. The perception has been that studies in relatively simple or evolutionarily ancient organisms would provide little insight into "complex" human biology. This perception, although always somewhat misguided, is now even less tenable given the results of the genome sequencing projects, which demonstrate that the human genome is remarkably similar to that of evolutionarily ancient organisms. Thus, the various life forms on Earth share much more in common then anyone had previously envisioned. This realization provides additional rationale for the use of nonclassical experimental models and provides perhaps the strongest validation of Bernard''s and Krogh''s assertions. This overview emphasizes some of the special attributes of alternative animal models that may be exploited to define the molecular and cellular basis of toxicity. For each attribute, selected examples of animal models and experimental approaches are presented. It focuses on the areas of neurotoxicology, reproductive and developmental toxicology, organ systems toxicology, carcinogenesis, and functional genomics/toxicogenomics and highlights the use of fish, avian, Drosophila, Caenorhabditis elegans, and yeast models in such studies.