+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

Permeation of large tetra-alkylammonium cations through mutant and wild-type voltage-gated sodium channels as revealed by relief of block at high voltage

Permeation of large tetra-alkylammonium cations through mutant and wild-type voltage-gated sodium channels as revealed by relief of block at high voltage

Journal of General Physiology 115(4): 435-454

Many large organic cations are potent blockers of K(+) channels and other cation-selective channels belonging to the P-region superfamily. However, the mechanism by which large hydrophobic cations enter and exit the narrow pores of these proteins is obscure. Previous work has shown that a conserved Lys residue in the DEKA locus of voltage-gated Na(+) channels is an important determinant of Na(+)/K(+) discrimination, exclusion of Ca(2+), and molecular sieving of organic cations. In this study, we sought to determine whether the Lys(III) residue of the DEKA locus interacts with internal tetra-alkylammonium cations (TAA(+)) that block Na(+) channels in a voltage-dependent fashion. We investigated block by a series of TAA(+) cations of the wild-type rat muscle Na(+) channel (DEKA) and two different mutants of the DEKA locus, DEAA and DERA, using whole-cell recording. TEA(+) and larger TAA(+) cations block both wild-type and DEAA channels. However, DEAA exhibits dramatic relief of block by large TAA(+) cations as revealed by a positive inflection in the macroscopic I-V curve at voltages greater than +140 mV. Paradoxically, relief of block at high positive voltage is observed for large (e.g., tetrapentylammonium) but not small (e.g., TEA(+)) symmetrical TAA(+) cations. The DEKA wild-type channel and the DERA mutant exhibit a similar relief-of-block phenomenon superimposed on background current rectification. The results indicate: (a) hydrophobic TAA(+) cations with a molecular diameter as large as 15 A can permeate Na(+) channels from inside to outside when driven by high positive voltage, and (b) the Lys(III) residue of the DEKA locus is an important determinant of inward rectification and internal block in Na(+) channels. From these observations, we suggest that hydrophobic interfaces between subunits, pseudosubunits, or packed helices of P-region channel proteins may function in facilitating blocker access to the pore, and may thus play an important role in the blocking and permeation behavior of large TAA(+) cations and potentially other kinds of local anesthetic molecules.

(PDF emailed within 0-6 h: $19.90)

Accession: 009936442

Download citation: RISBibTeXText

PMID: 10736311

DOI: 10.1085/jgp.115.4.435

Related references

Permeation of large tetra-alkylammonium cations through mutant and wild type Na-channels revealed by relief of block at high voltage. Biophysical Journal 78(1 Part 2): 144A, 2000

Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4. Journal of General Physiology 141(3): 309-321, 2013

Block of voltage-gated Ca-2+ channels in rat vascular smooth muscle by an alkylammonium derivative. Biophysical Journal 66(2 PART 2): A438, 1994

Downregulation of L-Type Voltage-Gated Ca2+, Voltage-Gated K+, and Large-Conductance Ca2+-Activated K+ Channels in Vascular Myocytes From Salt-Loading Offspring Rats Exposed to Prenatal Hypoxia. Journal of the American Heart Association 7(6), 2018

Cloning of a novel voltage gated sodium channel from human cardiac and skeletal muscle evidence for a new gene sub family of voltage gated sodium channels. Biophysical Journal 61(2 PART 2): A108, 1992

State-dependent block of rat brain type IIA voltage-gated sodium channels by phenoxyphenyl pyridines. Biophysical Journal 86(1): 117a, January, 2004

Mechanism of Ion Permeation in Mammalian Voltage-Gated Sodium Channels. Plos One 10(8): E0133000-E0133000, 2016

Simulation Studies of Ion Permeation and Selectivity in Voltage-Gated Sodium Channels. Current Topics in Membranes 78: 215-260, 2016

Voltage-clamp analysis of sodium channels in wild-type and mutant Drosophila neurons. Journal of Neuroscience 8(10): 3633-3643, 1988

Menthol pain relief through cumulative inactivation of voltage-gated sodium channels. Pain 153(2): 473-484, 2012

Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opinion on Therapeutic Targets 20(8): 975-983, 2016

Ion permeation through a voltage- sensitive gating pore in brain sodium channels having voltage sensor mutations. Neuron 47(2): 183-189, 2005

The pentapeptide QYNAD does not block voltage-gated sodium channels. Neurology 60(2): 224-229, 2003

Block of voltage-gated sodium channels by veratridine in the inner vestibule. Biophysical Journal 84(2 Part 2): 71a-72a, February, 2003

Voltage-gated sodium channels in sns null mutant mice. Society for Neuroscience Abstracts 24(1-2): 1821, 1998