Differential Association between HERG and KCNE1 or KCNE2

Abstract

The small proteins encoded by KCNE1 and KCNE2 have both been proposed as accessory subunits for the HERG channel. Here we report our investigation into the cell biology of the KCNE-HERG interaction. In a co-expression system, KCNE1 was more readily co-precipitated with co-expressed HERG than was KCNE2. When forward protein trafficking was prevented (either by Brefeldin A or engineering an ER-retention/retrieval signal onto KCNE cDNA) the intracellular abundance of KCNE2 and its association with HERG markedly increased relative to KCNE1. HERG co-localized more completely with KCNE1 than with KCNE2 in all the membrane-processing compartments of the cell (ER, Golgi and plasma membrane). By surface labeling and confocal immunofluorescence, KCNE2 appeared more abundant at the cell surface compared to KCNE1, which exhibited greater co-localization with the ER-marker calnexin. Examination of the extracellular culture media showed that a significant amount of KCNE2 was extracellular (both soluble and membrane-vesicle-associated). Taken together, these results suggest that during biogenesis of channels HERG is more likely to assemble with KCNE1 than KCNE2 due to distinctly different trafficking rates and retention in the cell rather than differences in relative affinity. The final channel subunit constitution, in vivo, is likely to be determined by a combination of relative cell-to-cell expression rates and differential protein processing and trafficking.

KCNE4 suppresses Kv1.3 currents by modulating trafficking, surface expression and channel gating

“…Thus, KCNE1 and KCNE2 associate with Kv1.5, and experiments with kcne2 null mice suggest that associations with Kv1.5 and Kv4.2, but not with Kv1.4 and Kv4.3, recapitulate cardiac I Kslow and I to,f (transient outward fast) currents Roepke et al, 2008 associations are crucial for KCNE1 expression at the plasma membrane (Chandrasekhar et al, 2006). In fact, KCNE1 shows greater ER retention than KCNE2 and this determines Kv11.1 association (Um and McDonald, 2007). KCNE4 also shows more ER retention than KCNE2.…”

“…3C, indicated that both proteins mostly share the same location. KCNE peptides are targeted to the cell surface with different efficiencies (Um and McDonald, 2007;Jiang et al, 2009). In this context, KCNE2 (Fig.…”

Glycine/Serine Polymorphism at Position 38 Influences KCNE1 Subunit’s Modulatory Actions on Rapid and Slow Delayed Rectifier K⁺ Currents

“…1-4 It is also shown that the KCNE1 subunit more efficiently assembles with the KCNH2 subunit than the KCNE2 subunit does, and this affects KCNH2 channel trafficking. 23 The KCNE1(38G) subunit is shown to augment KCNH2 and KCNQ1 channel currents, and this augmentation might contribute to maintaining normal channel function in cardiomyocytes. 1- 4 Our results indicate that the KCNH2 channel current augmentation effect of the KCNE1(38S) subunit is weaker than that of the KCNE1(38G) subunit.…”

KCNE2 and the K+channel

“…15,16 Surprisingly, KCNE2 is also thought to be secreted from the cell under some circumstances; 14 whether this is solely an in vitro phenomenon or one with physiological relevance that occurs in vivo, remains to be understood.…”

“…12,14,[71][72][73][74] In adult canine ventricular tissue, KCNE2 and cERG are colocalized in cholesterol and sphingolipid-enriched membrane fractions. 75 hERG (and ERG from other mammals) is unusual in that it is part of the S4 superfamily of voltage-gated ion www.landesbioscience.com Channelschannels that includes the Kv a subunits, but it exhibits inward rectification similar to the Kir subunits.…”