PMID: 11901231Mar 20, 2002Paper

Determinants of 4-aminopyridine sensitivity in a human brain kv1.4 k(+) channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed state

Molecular Pharmacology
S I JudgeC T Bever

Abstract

The biophysical and pharmacological effects of individual phenylalanine-for-leucine (Phe-for-Leu) substitutions in the leucine heptad repeat region located at the cytosolic surface of the channel pore, on whole-cell K(+) currents, were studied in cloned and mutated human brain Kvl.4 K(+) channels (hKvl.4) transiently transfected into HeLa cells. Although L2 and L5 are not considered part of the 4-aminopyridine (4-AP) binding site, unlike the L4 heptad leucine, Phe substitutions at L2 (L464) or L5 (L485) increase 4-AP sensitivity by 400-fold, as seen previously in the L4F mutant channel. Greater depolarizing shifts manifest in the voltage dependence of activation and inactivation in L2F (20 mV) and L5F (30 mV) than in L4F (10 mV) relative to hKv1.4. L1F (L457) and L3F (L471) increase 4-AP sensitivity by 8- and 150-fold, respectively, and produce depolarizing shifts in activation of approximately 5 mV without affecting inactivation. The apparent free energy differences of 4-AP binding in each mutant suggest enhanced drug-channel interactions (L2F > or = L4F > or = L5F > L3F > L1F). Deactivation kinetics are accelerated in L2F (11-fold), L5F (8-fold), L1F (5-fold), and L3F (2-fold), at -50 mV. All Phe-for-heptad-Leu substitutions ...Continue Reading

References

Apr 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·K McCormackB Rudy
Aug 3, 1989·Nature·W F Byerley
Nov 1, 1993·The Journal of General Physiology·G E Kirsch, J A Drewe
Jun 1, 1997·The Journal of General Physiology·C C ShiehG E Kirsch
Jul 21, 2001·Biophysical Journal·S SukharevH R Guy

❮ Previous
Next ❯

Citations

Jun 25, 2009·Expert Opinion on Investigational Drugs·Christopher T Bever, Susan Iv Judge
Feb 14, 2006·Pharmacology & Therapeutics·Susan I V Judge, Christopher T Bever
Sep 30, 2004·Biophysical Journal·Stewart R DurellH Robert Guy
Dec 21, 2002·The Journal of Biological Chemistry·Colin A SymeDaniel C Devor
Dec 14, 2004·CNS Drug Reviews·Keith C Hayes

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.