Role in fast inactivation of the IV/S4-S5 loop of the human muscle Na+ channel probed by cysteine mutagenesis

The Journal of Physiology
H LercheF Lehmann-Horn

Abstract

1. In order to investigate the role in fast inactivation of the cytoplasmic S4-S5 loop of the fourth domain (IV/S4-S5) within the alpha-subunit of the adult human muscle Na+ channel, every single amino acid from R1469 to G1486 was substituted by a cysteine and the mutants were studied by functional expression in human embryonic kidney cells (tsA201) using whole-cell patch clamping. Effects following intracellular application of the sulfhydryl reagents MTSET and MTSES on the mutants were investigated. 2. Sixteen of eighteen mutants resulted in the formation of functional channels. For P1480C and N1484C, no Na+ currents could be detected in transfected cells. In the absence of sulfhydryl reagents, F1473C and A1481C slowed fast Na+ channel inactivation by 2- and 1.5-fold, respectively, and L1482C induced a steady-state Na+ current (Iss) of 3% of peak current (Ipeak) (1% for wild-type). 3. Upon application of MTSET and MTSES, changes in fast inactivation gating occurred for most of the mutants. The most dramatic destabilizing effects on fast inactivation were observed for M1476C (9-fold slowing of inactivation; Iss/Ipeak, 3.6%; +15 mV shift in steady-state inactivation; 2- to 3-fold acceleration of recovery from inactivation), A148...Continue Reading

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Citations

Jul 10, 2003·Current Opinion in Neurobiology·Alan L Goldin
Apr 13, 2005·The Journal of General Physiology·Ya-Chin Yang, Chung-Chin Kuo
Apr 17, 2013·The Journal of General Physiology·James R Groome, Vern Winston
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Oct 2, 2004·The Journal of Physiology·M Oana PopaHolger Lerche
Dec 30, 2015·The Journal of General Physiology·Christopher A AhernBaron Chanda
Jan 25, 2006·British Journal of Pharmacology·Mariana Oana Popa, Holger Lerche
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Oct 3, 1999·Physiological Reviews·F Lehmann-Horn, K Jurkat-Rott

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