Temperature dependence of human <i>ether-à-go-go-</i>related gene K<sup>+</sup> currents

Vandenberg, Jamie I.; Varghese, Anthony; Lu, Yu; Bursill, Jane A.; Mahaut‐Smith, Martyn P.; Huang, Christopher L.‐H.

doi:10.1152/ajpcell.00596.2005

Cited by 119 publications

(152 citation statements)

References 63 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…A558P had little or no effect on HERG channel activation, recovery from inactivation, or deactivation. Our findings are in agreement with previous studies of WT HERG currents measured at room temperature and near-physiologic temperature (16,28). We believe this is the first report studying WT and mutant HERG currents at 40°C.…”

Section: Discussionsupporting

confidence: 93%

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Amin¹,

Herfst²,

Delisle³

et al. 2008

J. Clin. Invest.

View full text Add to dashboard Cite

Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.

show abstract

Section: Discussionsupporting

confidence: 93%

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Amin¹,

Herfst²,

Delisle³

et al. 2008

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…All data are shown as means Ϯ S.E. Measurements of steady state activation and inactivation were performed as previously described (28,30). Steady state activation and inactivation data were analyzed using a simple twostate Boltzmann function,…”

Section: Methodsmentioning

confidence: 99%

“…Typical examples of current traces recorded from oocytes expressing WT or L564A mutant hERG channels in response to a two-step voltage protocol designed to measure steady state inactivation (30) are illustrated in Fig. 4A.…”

Section: Mutants That Affect Steady State Inactivation Are Distributementioning

confidence: 99%

The Pore Domain Outer Helix Contributes to Both Activation and Inactivation of the hERG K+ Channel

Pagès

Riek

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Ion flow in many voltage-gated K؉ channels (VGK), including the (human ether-a-go-go-related gene) hERG channel, is regulated by reversible collapse of the selectivity filter. hERG channels, however, exhibit low sequence homology to other VGKs, particularly in the outer pore helix (S5) domain, and we hypothesize that this contributes to the unique activation and inactivation kinetics in hERG K ؉ channels that are so important for cardiac electrical activity. The S5 domain in hERG identified by NMR spectroscopy closely corresponded to the segment predicted by bioinformatics analysis of 676 members of the VGK superfamily. Mutations to approximately every third residue, from Phe 551 to Trp 563 , affected steady state activation, whereas mutations to approximately every third residue on an adjacent face and spanning the entire S5 segment perturbed inactivation, suggesting that the whole span of S5 experiences a rearrangement associated with inactivation. We refined a homology model of the hERG pore domain using constraints from the mutagenesis data with residues affecting inactivation pointing in toward S6. In this model the three residues with maximum impact on activation (W563A, F559A, and F551A) face out toward the voltage sensor. In addition, the residues that when mutated to alanine, or from alanine to valine, that did not express (Ala 561 , His 562 , Ala 565 , Trp 568 , and Ile 571 ), all point toward the pore helix and contribute to close hydrophobic packing in this region of the channel.

show abstract

“…Conversely, we exploited the rescued expression in oocytes to our advantage by measuring the gating properties of mutant channels in the oocyte expression system. These electrophysiological recordings were undertaken at room temperature, rather than at physiological temperature (37°C), which is known to slow gating kinetics (62). Even so, it is likely that the relative differences between WT and mutants will be similar in different expression systems, as shown previously for mutations F29L (14,18,63) and R56Q (14,(63)(64)(65).…”

Section: Effect Of Clinical Lqts2 Causing Mutations In the S1 Regionmentioning

confidence: 99%

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in finetuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11

show abstract

Temperature dependence of human ether-à-go-go-related gene K⁺ currents

Cited by 119 publications

References 63 publications

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

The Pore Domain Outer Helix Contributes to Both Activation and Inactivation of the hERG K+ Channel

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Contact Info

Product

Resources

About

Temperature dependence of human ether-à-go-go-related gene K+ currents

Cited by 119 publications

References 63 publications

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

The Pore Domain Outer Helix Contributes to Both Activation and Inactivation of the hERG K+ Channel

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Contact Info

Product

Resources

About

Temperature dependence of human ether-à-go-go-related gene K⁺ currents