Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.

Rationale: The mutation A341V in the S6 transmembrane segment of KCNQ1, the α-subunit of the slowly activating delayed-rectifier K(+) (I(Ks)) channel, predisposes to a severe long-QT1 syndrome with sympathetic-triggered ventricular tachyarrhythmias and sudden cardiac death.

Objective: Several genetic risk modifiers have been identified in A341V patients, but the molecular mechanisms underlying the pronounced repolarization phenotype, particularly during β-adrenergic receptor stimulation, remain unclear. We aimed to elucidate these mechanisms and provide new insights into control of cAMP-dependent modulation of I(Ks).

The S4-S5 linker of KCNQ1 channels forms a structural scaffold with the S6 segment controlling gate closure.

In vivo, KCNQ1 α-subunits associate with the β-subunit KCNE1 to generate the slowly activating cardiac potassium current (I(Ks)). Structurally, they share their topology with other Kv channels and consist out of six transmembrane helices (S1-S6) with the S1-S4 segments forming the voltage-sensing domain (VSD). The opening or closure of the intracellular channel gate, which localizes at the bottom of the S6 segment, is directly controlled by the movement of the VSD via an electromechanical coupling.

The rate-dependent biophysical properties of the LQT1 H258R mutant are counteracted by a dominant negative effect on channel trafficking.

The long QT syndrome (LQTS) is a cardiac disorder caused by a prolonged ventricular repolarization. The co-assembly of the pore-forming human KCNQ1 alpha-subunits with the modulating hKCNE1 beta-subunits generates I(Ks)in vivo, explaining why mutations in the hKCNQ1 gene underlie the LQT1 form of congenital LQT. Here we describe the functional defects of the LQT1 mutation H258R located in the S4-S5 linker, a segment important for channel gating.

Role of the S6 C-terminus in KCNQ1 channel gating.

Co-assembly of KCNQ1 alpha-subunits with KCNE1 beta-subunits results in the channel complex underlying the cardiac IKs current in vivo. Like other voltage-gated K+ channels, KCNQ1 has a tetrameric configuration. The S6 segment of each subunit lines the ion channel pore with the lower part forming the activation gate.

Functional effects of a KCNQ1 mutation associated with the long QT syndrome.

Objective: Long QT syndrome (LQTS) is an inherited disorder of ventricular repolarization caused by mutations in cardiac ion channel genes, including KCNQ1. In this study the electrophysiological properties of a LQTS-associated mutation in KCNQ1 (Q357R) were characterized. This mutation is located near the C-terminus of S6, a region that is important for the gate structure.