Modification of KCNH2-Encoded Cardiac Potassium Channels by KCNE1 Polymorphism

– Reply –

We thank Dr Hancox and his colleagues for their stimulating comments. As mentioned in their Letter, both their¹ and our² recent studies provide new insight into the pathogenic actions of KCNE1 subunit mutants. KCNE1 is primarily recognized as the β subunit of the slow delayed rectifier K⁺ current (I_Ks) channel whose pore-forming body consists of KCNQ1 subunits. Some mutations of the KCNE1 gene impair KCNE1’s modulatory actions on the I_Ks channel required for normal channel gating, and this impairment may lead to arrhythmic disorders.³ KCNE1 also interacts with the rapid delayed rectifier K⁺ current (I_Kr) channel whose pore-forming body consists of the human ether-à-go-go-related gene (hERG) subunits.⁴ However, it had remained unclear whether or not KCNE1 mutations influence I_Kr channel function until Dr Hancox’s and our groups independently demonstrated supportive evidence for this notion. The following are the main points drawn from these studies.

Dr Hancox’s group examined the effects of the naturally occurring KCNE1 mutants, KCNE1 (A8V), KCNE1 (D76N), and KCNE1 (D85N), on I_Kr channel function.¹ We compared the effects of the major and minor variants of the well-known polymorphism KCNE1 (38G) and KCNE1 (38S), respectively.² In heterologous expression systems, co-expression of the mutants or the minor variant decreases the whole-cell I_Kr density without changing the voltage-dependence of channel activation. For the mutants and variants, amino acid substitutions occur at different domains of the subunit. The site of A8V is located between the 2 α helices near the N-terminus, that of G38S near the initial part of the transmembrane domain, and those of D76N and D85N between the transmembrane domain and the C-terminal α helix.⁵ The fact that similar effects are observed for the different sites indicates that the integrity of the overall structure of KCNE1 might be important for normal modulatory action.

The KCNE1 mutants and minor variant may affect the I_Kr and I_Ks channels in different ways. For example, co-expression of KCNE1 (D76N) decreases the whole-cell current density but not the voltage-sensitivity of the I_Kr channel,¹ while decreasings both the current density and voltage-sensitivity of the I_Ks channel.⁶ As compared with KCNE1 (38G), co-expression of KCNE1 (38S) decreases the current density but not the voltage-sensitivity of the I_Kr channel, while decreasing the voltage-sensitivity but not the current density of the I_Ks channel.² The effects of the KCNE1 mutants and minor variant on I_Kr channel function might rely on a mechanism that differs from that underlying the effects on I_Ks channel function. Elucidation of the mechanism underlying the effects of KCNE1 mutants on I_Kr channel function is an important issue to be addressed in future.

Moreover, it turned out that the KCNE1 mutants and minor variant alter the susceptibility of the I_Kr channel to drugs that block the channel and thereby have arrhythmogenic side effects. Co-expression of KCNE1 (D76N) or KCNE1 (D85N) increases the susceptibility to clarithromycin, a macrolide antibiotic, lowering the IC₅₀ to 1/3–2/3, whereas that of KCNE1 (A8V) decreases the susceptibility, doubling the IC₅₀.¹ Co-expression of KCNE1 (A8V), KCNE1 (D76N), or KCNE1 (D85N) increases the susceptibility to cisapride, a gastric prokinetic drug, lowering the IC₅₀ to 1/2.¹ Co-expression of either of the mutants does not affect the susceptibility to quinidine, a class I antiarrhythmic drug.¹ As compared with KCNE1 (38G), co-expression of KCNE1 (38S) increases the susceptibility to E-4031, an experimental class III antiarrhythmic drug, lowering the apparent dissociation constant to 1/4.² The effects differ considerably, depending on the type of KCNE1 mutants/variant and drug.

In future studies, researchers and clinicians engaged in cardiac channelopathy should keep an eye out for the dual pathogenic actions of KCNE1 mutants via the I_Kr and I_Ks channels. In addition, the previously identified KCNE1 mutants, including ones that were judged to be ineffective on I_Ks channel function, await re-analysis in the light of their modulatory action on the I_Kr channel.

• Toshihide Tabata, PhD
• Laboratory for Neural Information Technology, Graduate School of Sciences and Engineering, University of Toyama, Toyama, Japan
• Yoshiaki Yamaguchi, MD
• Second Department of Internal Medicine, University of Toyama, Toyama, Japan
• Yukiko Hata, PhD
• Department of Legal Medicine, University of Toyama, Toyama, Japan
• Fukiko Ichida, MD, PhD
• Department of Pediatrics, University of Toyama, Toyama, Japan
• Hisashi Mori, PhD
• Department of Molecular Neurosciences, University of Toyama, Toyama, Japan

(Released online July 10, 2014)

References

• 1.    Du  C,  El Harchi  A,  Zhang  H,  Hancox  JC. Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition. Physiol Rep 2013; 1: e00175, doi:10.1002/phy2.175.
• 2.    Yamaguchi  Y,  Nishide  K,  Kato  M,  Hata  Y,  Mizumaki  K,  Kinoshita  K, et al. Glycine/serine polymorphism at position 38 influences KCNE1 subunit’s modulatory actions on rapid and slow delayed rectifier K⁺ currents. Circ J 2014; 78: 610–618.
• 3.    Dvir  M,  Peretz  A,  Haitin  Y,  Attali  B. Recent molecular insights from mutated I_KS channels in cardiac arrhythmia. Curr Opin Pharmacol 2014; 15: 74–82.
• 4.    Yang  T,  Kupershmidt  S,  Roden  DM. Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K⁺ current. Circ Res 1995; 77: 1246–1253.
• 5.    Kang  C,  Tian  C,  Sönnichsen  FD,  Smith  JA,  Meiler  J,  George  AL Jr, et al. Structure of KCEN1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry 2008; 47: 7999–8006.
• 6.    Chen  J,  Zheng  R,  Melman  YF,  McDonald  TV. Functional interactions between KCNE1 C-terminus and the KCNQ1 channel. PLoS One 2009; 4: e5143, doi:10.1371/journal.pone.0005143.