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• Articles by S.Y. Wang
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• Removal of sodium inactivation and block of sodium channels ...

  Removal of sodium inactivation and block of sodium channels by chloramine-T in crayfish and squid giant axons Biophysical Journal, Volume 52, Issue 2, 1 August 1987, Pages 155-163 J.M. Huang, J. Tanguy and J.Z. Yeh Abstract Modification of sodium channels by chloramine-T was examined in voltage clamped internally perfused crayfish and squid giant axons using the double sucrose gap and axial wire technique, respectively. Freshly prepared chloramine-T solution exerted two major actions on sodium channels: (a) an irreversible removal of the fast Na inactivation, and (b) a reversible block of the Na current. Both effects were observed when chloramine-T was applied internally or externally (5–10 mM) to axons. The first effect was studied in crayfish axons. We found that the removal of the fast Na inactivation did not depend on the states of the channel since the channel could be modified by chloramine-T at holding potential (from -80 to -100 mV) or at depolarized potential of -30 mV. After removal of fast Na inactivation, the slow inactivation mechanism was still present, and more channels could undergo slow inactivation. This result indicates that in crayfish axons the transition through the fast inactivated state is not a prerequisite for the slow inactivation to occur. During chloramine-T treatment, a distinct blocking phase occurred, which recovered upon washing out the drug. This second effect of chloramine-T was studied in detail in squid axons. After 24 h, chloramine-T solution lost its ability to remove fast inactivation but retained its blocking action. After removal of the fast Na inactivation, both fresh and aged chloramine-T solutions blocked the Na currents with a similar potency and in a voltage-dependent manner, being more pronounced at lower depolarizing potentials.(ABSTRACT TRUNCATED AT 250 WORDS) Abstract | PDF (1145 kb)

• QX-314 restores gating charge immobilization abolished by ch...

  QX-314 restores gating charge immobilization abolished by chloramine-T treatment in squid giant axons Biophysical Journal, Volume 56, Issue 2, 1 August 1989, Pages 421-427 J. Tanguy and J.Z. Yeh Abstract The gating status of the QX-314 bound Na channels before and after suppressing the fast inactivation by chloramine-T (CT) was investigated by studying the gating charge immobilization using the OFF gating current (Ig,OFF). CT treatment, which abolishes the charge immobilization induced by a prolonged depolarization, altered the kinetics of Ig,OFF: the fast phase became insensitive to the pulse duration and the slow phase became three times faster than the control one. However, internally applied QX-314 (in the presence of external TTX) caused an immediate charge immobilization similar to that observed in the absence of CT treatment. The Ig,OFF exhibited kinetics similar to the inactivated channels, decaying with a very fast time course. We conclude that the charge immobilization is restored by QX-314 in the chloramine-T-treated axon and that the gating state of the QX-314-bound channel is similar to the inactivated one. The role of the gating charge immobilization in the use-dependent block mechanism is discussed. Abstract | PDF (780 kb)

• Batrachotoxin uncouples gating charge immobilization from fa...

  Batrachotoxin uncouples gating charge immobilization from fast Na inactivation in squid giant axons Biophysical Journal, Volume 54, Issue 4, 1 October 1988, Pages 719-730 J. Tanguy and J.Z. Yeh Abstract The fast inactivation of sodium currents and the immobolization of sodium gating charge are thought to be closely coupled to each other. This notion was tested in the squid axon in which kinetics and steady-state properties of the gating charge movement were compared before and after removal of the Na inactivation by batrachotoxin (BTX), pronase, or chloramine-T. The immobilization of gating charge was determined by measuring the total charge movement (QON) obtained by integrating the ON gating current (Ig,ON) using a double pulse protocol. After removal of the fast inactivation with pronase or chloramine-T, the gating charge movement was no longer immobilized. In contrast, after BTX modification, the channels still exhibited an immobilization of the gating charge (QON) with an onset time course and voltage dependence similar to that for the activation process. These results show that BTX can uncouple the charge immobilization from the fast Na inactivation mechanism, suggesting that the Na gating charge movement can be immobilized independently of the inactivation of the channel. Abstract | PDF (1439 kb)

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Abstract

Slow inactivation occurs in voltage-gated Na+ channels when the membrane is depolarized for several seconds, whereas fast inactivation takes place rapidly within a few milliseconds. Unlike fast inactivation, the molecular entity that governs the slow inactivation of Na+ channels has not been as well defined. Some regions of Na+ channels, such as mu1-W402C and mu1-T698M, have been reported to affect slow inactivation. A mutation in segment I-S6 of mu1 Na+ channels, N434A, shifts the voltage dependence of activation and fast inactivation toward the depolarizing direction. The mutant Na+ current at +50 mV is diminished by 60–80% during repetitive stimulation at 5 Hz, resulting in a profound use-dependent phenomenon. This mutant phenotype is due to the enhancement of slow inactivation, which develops faster than that of wild-type channels (tau = 0.46 +/- 0.01 s versus 2.11 +/- 0.10 s at +30 mV, n = 9). An oxidant, chloramine-T, abolishes fast inactivation and yet greatly accelerates slow inactivation in both mutant and wild-type channels (tau = 0.21 +/- 0.02 s and 0.67 +/- 0.05 s, respectively, n = 6). These findings together demonstrate that N434 of mu1 Na+ channels is also critical for slow inactivation. We propose that this slow form of Na+ channel inactivation is analogous to the "C-type" inactivation in Shaker K+ channels.