BACKGROUND: The transient outward current I(to) is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary beta subunit KCNE2 recently was shown to modulate I(to). OBJECTIVE: The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I(to). METHODS: The functional interaction between Kv4.3 (alpha subunit of human I(to)) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques. RESULTS: Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I(to). Both M54T and I57T variants significantly increased I(to) current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation. CONCLUSION: The study results suggest that KCNE2 plays a critical role in the normal function of the native I(to) channel complex in human heart and that M54T and I57T variants lead to a gain of function of I(to), which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.
BACKGROUND: The transient outward current I(to) is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary beta subunit KCNE2 recently was shown to modulate I(to). OBJECTIVE: The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I(to). METHODS: The functional interaction between Kv4.3 (alpha subunit of human I(to)) and wild-type (WT), M54T, and I57TKCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques. RESULTS: Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I(to). Both M54T and I57T variants significantly increased I(to) current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation. CONCLUSION: The study results suggest that KCNE2 plays a critical role in the normal function of the native I(to) channel complex in human heart and that M54T and I57T variants lead to a gain of function of I(to), which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.
Authors: Kirstine Calloe; Jonathan M Cordeiro; José M Di Diego; Rie S Hansen; Morten Grunnet; Søren Peter Olesen; Charles Antzelevitch Journal: Cardiovasc Res Date: 2008-12-10 Impact factor: 10.787
Authors: Eva Delpón; Jonathan M Cordeiro; Lucía Núñez; Poul Erik Bloch Thomsen; Alejandra Guerchicoff; Guido D Pollevick; Yuesheng Wu; Jørgen K Kanters; Carsten Toftager Larsen; Jacob Hofman-Bang; Elena Burashnikov; Michael Christiansen; Charles Antzelevitch Journal: Circ Arrhythm Electrophysiol Date: 2008-08
Authors: Can Hasdemir; Figen Gokcay; Mehmet N Orman; Umut Kocabas; Serdar Payzin; Hatice Sahin; Dale R Nyholt; Charles Antzelevitch Journal: J Cardiovasc Electrophysiol Date: 2020-10-23
Authors: Yoann Lussier; Oliver Fürst; Eva Fortea; Marc Leclerc; Dimitri Priolo; Lena Moeller; Daniel G Bichet; Rikard Blunck; Nazzareno D'Avanzo Journal: Sci Rep Date: 2019-06-24 Impact factor: 4.379