TY - BOOK

T1 - Trafficking and intracellular regulation of Kv7.1 potassium channels in the heart

AU - Nielsen, Nathalie Hélix

PY - 2008

Y1 - 2008

N2 - The electrical activity of the heart, measured by application of surface body electrodes and recorded as an electrocardiogram, is the result of a finely tuned balance of ion movement (K+, Na+, Ca2+). The ionic currents collectively constitute the cardiac action potential created in the cell membrane and spreading throughout the different regions of the heart. Any disturbance of the ionic currents underlying the cardiac action potential can give rise to heart failure. The cardiac action potential is composed of five different phases: An initial fast depolarization, a partial repolarization or “notch”, a plateau, a full repolarization and finally a resting phase. Potassium channels are involved in the stabilization of the resting membrane potential of the cardiomyocytes but they are also the major component of the repolarization phase.Two repolarizing potassium currents have been identified: a fast (IKr) and a slower one (IKs). Impairment of either current gives rise to prolongation of the action potential duration and thus may induce the so-called Long QT Syndrome. KCNH2 is the molecular component of the IKr current whereas the association of the KCNQ1 and KCNE1 gene products (Kv7.1 and KCNE1 proteins) encode for the IKs current. KCNE1 is a b-subunit that associates with the Kv7.1 channel and changes its electrical properties. Mutations in the KCNQ1 gene are the most common cause of congenital Long QT Syndrome; specifically it causes the Long QT Syndrome 1. The repolarization abnormalities induced by “loss of function” Kv7.1 mutations increase the risk of polymorphic ventricular arrhythmias. These cardiac arrhythmias, typically in the form of torsades de pointes, may underlie ventricular fibrillation, recurrent syncope, and sudden death. To date, nearly 300 Kv7.1 mutations have been identified. About 100 of these mutations are located in the N- or the C-terminal parts of the channel.The aim of the present work was to gain a better understanding of the Kv7.1 channel protein function.In the first study we identified a Kv7.1 missense mutation in a German family with Long QT Syndrome. The mutation is located in the C-terminus of the Kv7.1 channel protein in a calmodulin binding domain, where the methionine (M) at position 520 is replaced by an arginine (R). Our results show that although Kv7.1/calmodulin interaction is not impaired by the M520R mutation, the mutated channels are retained in the ER. The amount of channels available in the plasma membrane is then reduced, leading to an impaired repolarization current and in consequence a prolongation of the action potential.In the second study we identified FHL2 (Four and a Half LIM protein 2), a heart specific scaffolding protein, as an interaction partner of the Kv7.1 channel. Though Kv7.1 or IKs currents did not appear to be directly affected by FHL2, we demonstrated that FHL2 is involved in the rescue of some disease associated KCNE1 mutants (D76N and S74L). Finally our data suggest that the MAP kinase 3 (MAPK3 or ERK1/2) contributes to the regulation of the Kv7.1 channel, which displays a consensus site in the N-terminus for this kinase.Our study, with the support of others, tends to demonstrate that the Kv7.1 channel forms a macromolecular signaling complex with its interactions partners in order to allow a fast response to external signals.

AB - The electrical activity of the heart, measured by application of surface body electrodes and recorded as an electrocardiogram, is the result of a finely tuned balance of ion movement (K+, Na+, Ca2+). The ionic currents collectively constitute the cardiac action potential created in the cell membrane and spreading throughout the different regions of the heart. Any disturbance of the ionic currents underlying the cardiac action potential can give rise to heart failure. The cardiac action potential is composed of five different phases: An initial fast depolarization, a partial repolarization or “notch”, a plateau, a full repolarization and finally a resting phase. Potassium channels are involved in the stabilization of the resting membrane potential of the cardiomyocytes but they are also the major component of the repolarization phase.Two repolarizing potassium currents have been identified: a fast (IKr) and a slower one (IKs). Impairment of either current gives rise to prolongation of the action potential duration and thus may induce the so-called Long QT Syndrome. KCNH2 is the molecular component of the IKr current whereas the association of the KCNQ1 and KCNE1 gene products (Kv7.1 and KCNE1 proteins) encode for the IKs current. KCNE1 is a b-subunit that associates with the Kv7.1 channel and changes its electrical properties. Mutations in the KCNQ1 gene are the most common cause of congenital Long QT Syndrome; specifically it causes the Long QT Syndrome 1. The repolarization abnormalities induced by “loss of function” Kv7.1 mutations increase the risk of polymorphic ventricular arrhythmias. These cardiac arrhythmias, typically in the form of torsades de pointes, may underlie ventricular fibrillation, recurrent syncope, and sudden death. To date, nearly 300 Kv7.1 mutations have been identified. About 100 of these mutations are located in the N- or the C-terminal parts of the channel.The aim of the present work was to gain a better understanding of the Kv7.1 channel protein function.In the first study we identified a Kv7.1 missense mutation in a German family with Long QT Syndrome. The mutation is located in the C-terminus of the Kv7.1 channel protein in a calmodulin binding domain, where the methionine (M) at position 520 is replaced by an arginine (R). Our results show that although Kv7.1/calmodulin interaction is not impaired by the M520R mutation, the mutated channels are retained in the ER. The amount of channels available in the plasma membrane is then reduced, leading to an impaired repolarization current and in consequence a prolongation of the action potential.In the second study we identified FHL2 (Four and a Half LIM protein 2), a heart specific scaffolding protein, as an interaction partner of the Kv7.1 channel. Though Kv7.1 or IKs currents did not appear to be directly affected by FHL2, we demonstrated that FHL2 is involved in the rescue of some disease associated KCNE1 mutants (D76N and S74L). Finally our data suggest that the MAP kinase 3 (MAPK3 or ERK1/2) contributes to the regulation of the Kv7.1 channel, which displays a consensus site in the N-terminus for this kinase.Our study, with the support of others, tends to demonstrate that the Kv7.1 channel forms a macromolecular signaling complex with its interactions partners in order to allow a fast response to external signals.

M3 - Ph.D. thesis

BT - Trafficking and intracellular regulation of Kv7.1 potassium channels in the heart

PB - Museum Tusculanum

ER -