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Experimental and molecular pathology (1)
Nature communications (1)
Bosmans, Frank (2)
Gilchrist, John (2)
Bende, Niraj S (1)
Dziemborowicz, Slawomir (1)
Early, Merideth A. (1)
Gilchrist, John M. (1)
Gonzalez-Juarerro, Mercedes (1)
Herzig, Volker (1)
Higgins, David M. (1)
King, Glenn F (1)
Lishnevsky, Marta (1)
Mobli, Mehdi (1)
Muller, William A. (1)
Nicholson, Graham M (1)
Orme, Ian M. (1)
Schenkel, Alan R. (1)
Wagner, Jordan (1)
Year of Publication
A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a
Bende, Niraj S
Nicholson, Graham M
King, Glenn F
β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1–S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, aconcept that will be valuable for the design of insect-selective insecticides.
voltage-gated sodium channel; voltage sensor; spider toxin; Dc1a; insect; cockroach
Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9
Human voltage-activated sodium (Nav) channels are adept at rapidly transmitting electrical signals across long distances in various excitable tissues. As such, they are amongst the most widely targeted ion channels by drugs and animal toxins. Of the nine isoforms, Nav1.8 and Nav1.9 are preferentially expressed in DRG neurons where they are thought to play an important role in pain signaling. Although the functional properties of Nav1.8 have been relatively well characterized, difficulties with expressing Nav1.9 in established heterologous systems limit our understanding of the gating properties and toxin pharmacology of this particular isoform. This review summarizes our current knowledge of the role of Nav1.8 and Nav1.9 in pain perception and elaborates on the approaches used to identify molecules capable of influencing their function.
Nav1.8; Nav1.9; pain; animal toxins; voltage sensor; voltage-activated sodium channel
Non-invasive Diagnosis of Early Pulmonary Disease in PECAM Deficient Mice Using Infrared Pulse Oximetry
Early, Merideth A.
Higgins, David M.
Orme, Ian M.
Muller, William A.
Schenkel, Alan R.
Experimental and molecular pathology
Pulse oximetry is a common tool for detecting reduced pulmonary function in human interstitial lung diseases. It has not previously been used in a mouse model of interstitial lung disease. Further, Platelet Endothelial Cell Adhesion Molecule deficient mice rarely show symptoms until disease is advanced.
Using blood oxygen saturation, different stages of disease could be identified in a non-invasive manner. These stages could be correlated to pathology. Collagen deposition, using Picrosirius Red, did correlate with blood oxygen saturation. These studies are the first to show the use of an infrared pulse oximetry system to analyze the progression of a fibrotic interstitial lung disease in a mouse model of the human diseases. Further, these studies show that an early alveolar damage/enlargement event precedes the fibrosis in this mouse model, a stage that represents the best targets for disease analysis and prevention. This stage does not have extensive collagen deposition. Most importantly, targeting this earliest stage of disease for therapeutic intervention may lead to novel treatment for human disease.
PECAM; lung; fibrosis; blood; oxygen
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