Delayed KCNQ1/KCNE1 assembly on the cell surface helps I_Ks fulfil its function as a repolarization reserve in the heart

Abstract

In adult ventricular myocytes, the slow delayed rectifier (I Ks ) channels are distributed on the surface sarcolemma, not t-tubules.r In adult ventricular myocytes, KCNQ1 and KCNE1 have distinct cell surface and cytoplasmic pools.r KCNQ1 and KCNE1 traffic from the endoplasmic reticulum to the plasma membrane by separate routes, and assemble into I Ks channels on the cell surface.r Liquid chromatography/tandem mass spectrometry applied to affinity-purified KCNQ1 and KCNE1 interacting proteins reveals novel interactors involved in protein trafficking and assembly.r Microtubule plus-end binding protein 1 (EB1) binds KCNQ1 preferentially in its dimer form, and promotes KCNQ1 to reach the cell surface.r An LQT1-associated mutation, Y111C, reduces KCNQ1 binding to EB1 dimer.

Routing of Kv7.1 to endoplasmic reticulum plasma membrane junctions

“…The Kv7.1 channel routes to the cell surface by an unconventional mechanism – bypassing the Golgi apparatus – which drives the channel via ER‐PMjs to the cell membrane 7,8 . Thus, Brefeldin, which suppresses the canonical Golgi‐dependent anterograde route, did not alter Kv7.1 ER localization (Figure S2A,B).…”

“…This K + current is crucial for the termination of cardiac action potentials. The association takes place in ER‐PMjs before translocation to the plasma membrane 7,8 . Thus, the I Ks channel, expressed in the sarcolemma as well as its contact sites with the SR, is located in the characteristic T‐tubule structures, which house the ion channel machinery for excitation‐contraction (E‐C) coupling.…”

“…However, recent studies suggest that Kv7.1 and KCNE1 route separately to the cell surface and then interact in endoplasmic reticulum‐plasma membrane junctions (ER‐PMjs). Advanced technologies demonstrate that while KCNE1 travels to these locations by a canonical anterograde route via the Golgi apparatus, Kv7.1 uses a noncanonical path to reach the plasma membrane 7,8 . Therefore, these ER‐PMjs, which are plasma membrane to endoplasmic reticulum contact sites, are hot spots for investigating the I Ks complex interactions.…”

Mechanisms and Regulation of Cardiac CaV1.2 Trafficking

“…The addition of biotin outcompetes the SBP/streptavidin interaction and severs the connection between the hook and bait allowing the protein to be released into the secretory pathway. This system has recently been used to study glutamate receptor [151], KCNQ1/KCNE1 [152], and to study altered transport kinetics during pathological conditions [153]. One could envisage that this system could be used to determine when and where the various auxiliary subunits of the channel join the α1 subunit.…”

Remodeling of Ion Channel Trafficking and Cardiac Arrhythmias

“…In this context, real-time study of channel and partner (co-)trafficking should help understand whether interactions with and/or competition between different channel partners during intracellular trafficking steps direct the final destination of ion channels. Recently, using cutting-edge live-imaging technologies, the group of Tseng showed that KCNQ1 and KCNE1 traffic through separate routes and only assemble at the sarcolemma to form I Ks [ 35 ]. Furthermore, to understand the development of arrhythmias associated upstream or downstream of myocardial remodeling, the question of the interplay between electrical and structural polarization must be addressed.…”