Block of tetrodotoxin-resistant Na+ channel pore by multivalent cations: gating modification and Na+ flow dependence

The Journal of General Physiology
Chung-Chin KuoYa-Chin Yang

Abstract

Tetrodotoxin-resistant (TTX-R) Na(+) channels are much less susceptible to external TTX but more susceptible to external Cd(2+) block than tetrodotoxin-sensitive (TTX-S) Na(+) channels. Both TTX and Cd(2+) seem to block the channel near the "DEKA" ring, which is probably part of a multi-ion single-file region adjacent to the external pore mouth and is involved in the selectivity filter of the channel. In this study we demonstrate that other multivalent transitional metal ions such as La(3+), Zn(2+), Ni(2+), Co(2+), and Mn(2+) also block the TTX-R channels in dorsal root ganglion neurons. Just like Cd(2+), the blocking effect has little intrinsic voltage dependence, but is profoundly influenced by Na(+) flow. The apparent dissociation constants of the blocking ions are always significantly smaller in inward Na(+) currents than those in outward Na(+) current, signaling exit of the blocker along with the Na(+) flow and a high internal energy barrier for "permeation" of these multivalent blocking ions through the pore. Most interestingly, the activation and especially the inactivation kinetics are slowed by the blocking ions. Moreover, the gating changes induced by the same concentration of a blocking ion are evidently different in...Continue Reading

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Citations

Jul 1, 2004·The Journal of General Physiology·Robert S Kass
Apr 13, 2005·The Journal of General Physiology·Ya-Chin Yang, Chung-Chin Kuo
Dec 2, 2004·The Journal of General Physiology·Carlos A Obejero-PazStephen W Jones
Dec 2, 2004·The Journal of General Physiology·Emilio Carbone
Jul 4, 2009·Regional Anesthesia and Pain Medicine·Yu-Chun HungPeter Gerner
Mar 24, 2009·PloS One·Alison R Taylor
Nov 4, 2006·The Journal of Physiology·Achraf TraboulsiePhilippe Lory
Dec 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Joshua B BrettmannKatherine A Henzler-Wildman
May 12, 2006·Journal of Cardiovascular Electrophysiology·Robert S Kass
Jul 8, 2016·International Journal of Molecular Sciences·Francisco Andrés Peralta, Juan Pablo Huidobro-Toro
Sep 27, 2005·Physiological Reviews·Werner Ulbricht
May 24, 2011·The Journal of Biological Chemistry·Wei YangLin-Hua Jiang
Jul 3, 2019·Molecular Pharmacology·Allison L GermannGustav Akk
Oct 17, 2017·Frontiers in Cellular Neuroscience·Laura J Blakemore, Paul Q Trombley
Jan 18, 2006·Pharmacology & Therapeutics·Alistair MathieEmma L Veale
Nov 10, 2021·Clinical and Experimental Pharmacology & Physiology·Bartłomiej SzulczykMaciej Gawlak

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