The KCNE2 K⁺ channel regulatory subunit: Ubiquitous influence, complex pathobiology

Abstract

The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and functionally regulating the voltage-gated potassium channels, the broad influence of KCNE subunits in mammalian physiology belies their small size. KCNE2 has been widely studied since we first discovered one of its roles in the heart and its association with inherited and acquired human Long QT syndrome. Since then, physiological analyses together with human and mouse genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. The other side of this coin is the variety of interconnected disease manifestations caused by KCNE2 disruption, involving both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia. Kcne2 deletion in mice has been particularly instrumental in illustrating the potential ramifications within a monogenic arrhythmia syndrome, with removal of one piece revealing the unexpected complexity of the puzzle. Here, we review current knowledge of the function and pathobiology of KCNE2.

Keywords: Cardiac arrhythmia; Potassium channel; Sudden cardiac death; Thyroid; Transporter.

Figure 1. KCNE2 regulates hERG

A. Cartoon of a Kvα-KCNE subunit complex in the plasma membrane (green) showing a 4:2 subunit stoichiometry. B. Effect of KCNE2 on hERG in Xenopus oocyte expression studies, measured by two-electrode voltage clamp with 100 mM KCl bath solution. Voltage protocol shown at top. Adapted from . KCNE2 reduces hERG unitary and macroscopic conductance and accelerates its deactivation.

Figure 2. Sequences and disease associations of the human KCNE family

Human KCNE protein sequences shown with features highlighted. Disease associations color-coded: AF, atrial fibrillation; BrS, Brugada Syndrome; LQTS, Long QT Syndrome. Adapted from a figure prepared by Dr. Shawn Crump in .

Figure 3. KCNQ1 and KCNE2 form constitutively active gastric K⁺ channels

A. Effects of KCNE2 on KCNQ1 in Xenopus oocyte expression studies measured by two-electrode voltage clamp with 4 mM KCl bath solution. Voltage protocol shown at top. KCNE2 greatly slows KCNQ1 deactivation and/or left-shifts its voltage dependence of activation, and decreases current density. B. The role of KCNQ1-KCNE2 in parietal cells. Adapted from . D cell, somatostatin-producing cell; E2, KCNE2; ECL, enterochromaffin-like; G cell, Guard cell; HKA, H⁺/K⁺-ATPase; Kir, inward rectifier K⁺ channels; NBC, Na⁺/HCO₃⁻ co-transporter; NHE, sodium/hydrogen exchanger; NKA, Na⁺/K⁺-ATPase; NKCC1, Na⁺/K⁺/2Cl⁻ co-transporter 1; Q1, KCNQ1; SLC, solute carrier transporter. C. KCNE3 upregulation caused by Kcne2 gene deletion rewires parietal cells. In the absence of KCNE2, KCNE3 traffics KCNQ1 to the basolateral membrane, where it cannot perform its normal function of allowing K⁺ back into the stomach lumen. When both Kcne2 and KCne3 are germline-deleted, KCNQ1 defaults to the apical membrane but does not function properly without KCNE2. From .

Figure 4. KCNQ1 and KCNE2 form constitutively active thyroid and choroid plexus K⁺ channels

A. KCNQ1-KCNE2 in thyroid epithelial cells. Adapted from . E2, KCNE2; Q1, KCNQ1; NIS, sodium/iodide symporter; T₃, triiodothyronine; T₄, thyroxine. B. Model of the role of KCNQ1-KCNE2 in choroid plexus epithelial cells. Updated from . AC, anion channel; AQP, aquaporin; CPe, choroid plexus epithelium; E2, KCC, K⁺Cl⁻ co-transporter; KCNE2; Kir, inward rectifier K⁺ channels; NBC, Na⁺/HCO₃⁻ co-transporter; NHE, sodium/hydrogen exchanger; NKA, Na⁺/K⁺-ATPase; Q1, KCNQ1; SMIT1, Na⁺-dependent myo-inositol transporter.

Figure 5. KCNQ1 and the human ventricular myocyte action potential

A. Idealized ventricular action potential showing when specific ionic currents are influential. Inset, the QT interval on a human body surface electrocardiogram. Adapted from . B. Effect of KCNE1 on KCNQ1 in Xenopus oocyte expression studies measured by two-electrode voltage clamp with 4 mM KCl bath solution. Voltage protocol shown upper left. KCNE1 slows KCNQ1 activation, right-shifts the voltage dependence of activation, and increases unitary conductance.

Figure 6. Role of KCNE2 in determining Kv α subunit trafficking and subunit composition

A. KCNE2 (E2) can reach the plasma membrane without the assistance of α subunit partners, whereas KCNE1 (E1) and KCNE3 (E3) require them. B. KCNE2 (E2) can retain N-type inactivating α subunits (Kv1.4, Kv3.3 and Kv3.4) in the Golgi and/or endoplasmic reticulum, preventing surface expression of homomeric N-type channels. Same-subfamily delayed-rectifier α subunits can rescue the N-type α subunits, ensuring mixed-α complexes reach the cell surface. It is not clear whether KCNE2 travels to the surface within these mixed complexes (upper left)^,. C. In some polarized cell types, KCNEs can dictate α subunit localization. In parietal cells, KCNQ1 traffics to the apical surface alone or with KCNE2 (E2), but if KCNE3 (E3) is expressed in the absence of KCNE2, the resultant KCNQ1-KCNE3 channels travel to the basolateral membrane. D. KCNE2 (E2) and KCNE1 (not shown) can mediate forms of α subunit turnover not necessarily observed for the α subunit alone. KCNE2 accelerates hERG protein degradation, possibly involving increased hERG internalization from the membrane.