Pharmacological and biophysical characterization of a prokaryotic voltage-gated sodium channel
The pedigree of voltage-gated sodium channels spans the millennia from eukaryotic members that initiate the action potential firing in excitable tissues to primordial ancestors that act as enviro-protective complexes in bacterial extremophiles. Eukaryotic sodium channels (eNavs) are central to elect...
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| Format: | Others |
| Language: | English |
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University of Iowa
2014
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| Online Access: | https://ir.uiowa.edu/etd/1477 https://ir.uiowa.edu/cgi/viewcontent.cgi?article=5553&context=etd |
| Summary: | The pedigree of voltage-gated sodium channels spans the millennia from eukaryotic members that initiate the action potential firing in excitable tissues to primordial ancestors that act as enviro-protective complexes in bacterial extremophiles. Eukaryotic sodium channels (eNavs) are central to electrical signaling throughout the cardiovascular and nervous systems in animals and are established clinical targets for the therapeutic management of epilepsy, cardiac arrhythmia and painful syndromes as they are inhibited by local anesthetic compounds. Alternatively, bacterial voltage-gated sodium channels (bNavs) likely regulate the survival response against extreme pH conditions, electrophiles and hypo-osmotic shock and may represent a founder of the voltage-gated cation channel family. Despite apparent differences between eNav and bNav channel physiology, gating and gene structure, the discovery that bNavs are amenable to crystallographic study opens the door for the possibility of structure-guided rational design of the next generation of therapeutics that target eNavs. Here I summarize the gating behavior of a bacterial channel NaChBac and discuss mechanisms of local anesthetic inhibition in light of the growing number of bNav structures. Also, an interesting novel observation on cross-lineage modulation of NaChBac by eNav beta subunit is reported. This auxiliary subunit modulation is isoform specific and I show the discrete effects of each isoforms on NaChBac, with functional and biochemical analysis. I also report a novel mutation that alters inactivation kinetic drastically and a possible mechanism of NaChBac inactivation is discussed. |
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