Structure Function Analysis Of Sodium Channels

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Structure Function Analysis of Sodium Channels in Human iPSC-derived Neurons Keywords: iPSC, sodium channel, electrophysiology, neuron, inactivation Background: Neuronal excitability mediated by sodium-dependent action potentials (APs) is required for rapid and specific communication in our brains. This underlies our ability to sense and respond to stimuli and for higher order cognitive functions including learning and memory. Voltage gated sodium channels (NaVs) open in response to membrane depolarization and initiate the AP. The α subunit is the major functional unit of NaVs and is comprised of 4 homologous domains (DI-DIV), each containing 6 transmembrane segments (S1-6)4,5. S4, the voltage sensor that detects depolarization, contains 4-8 positively charged amino acids each separated by two hydrophobic residues4,6. The positive charges on S4 are pushed outward by the electric field during membrane depolarization leading to channel opening, allowing influx of positively charged sodium ions down their concentration gradient4. Fast inactivation helps return the membrane to rest by blocking the conductance of sodium ions through the channel pore 1,2. Studies in expression systems suggest that the DIVS4 plays a unique role in inactivation1,2,3,6. Recent wholeWhole genome sequencing data associated with human disease identify other potentially important amino acid in the DIVS45,8. Two mutations of the 4th positive charge in DIVS4 (aka 4R4), 4R4H (arginine to histidine) and
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