KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation

Abstract

The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE subunits appears to be regulation of voltage-gated potassium (Kv) channels, and the best-understood KCNE complexes are with the KCNQ1 Kv α subunit. Here, we review the often opposite effects of KCNE1 and KCNE3 on Kv channel biology, with an emphasis on regulation of KCNQ1. Slow-activating IKs channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways. Because of their contrasting effects on KCNQ1 function, KCNE1 and KCNE3 have proved invaluable tools in the mechanistic understanding of how channel gating can be manipulated, and each may also provide a window into novel insights and new therapeutic opportunities in K(+) channel pharmacology. Finally, findings from studies of Kcne1(-/-) and Kcne3(-/-) mouse lines serve to illustrate the complexity of KCNE biology and KCNE-linked disease states.

Keywords: Auditory; Cardiac arrhythmia; Inherited deafness; Intestine; Long QT syndrome; Potassium channel; Voltage-gated.

Figure 1. The KCNE gene family

A. Left, Topology diagram of a 6TM spanning Kv α subunit with voltage sensing domain (VSD) and pore domain highlighted. Right, 1TM topology of a KCNE subunit. Ext, extracellular; Int, intracellular. B. 4:2 α:β stoichiometry of a KCNQ1-KCNE1 complex. C. Sequence alignment of the KCNE gene family. Transmembrane (TM) domain boxed; highly conserved residues/features indicated with gray shading.

Figure 2. Functional effects of KCNE1 and KCNE3 on KCNQ1

Example traces recorded by two-electrode voltage clamp from oocytes injected with cRNA encoding KCNQ1 alone or with KCNE1 or KCNE3. Voltage protocol shown at top. Scale bars: vertical, 2 μA; horizontal, 1s. Dotted line indicates zero current level. Traces are from ^and .

Figure 3. Mechanisms of KCNE1 and KCNE3 control of KCNQ1 gating and conductance

A. Topology diagrams of KCNQ1 with KCNE1 (upper) and KCNE3 (lower) showing residues (numbered where specific residues have been identified as particularly important) and domains identified as being influential in control of KCNQ1 gating by the KCNEs. Arrows: red, KCNE1 or 3 control of KCNQ1 activation; yellow, KCNE1 control of deactivation; orange, KCNE1 control of inactivation; pink, KCNE1 control of conductance; purple, inter-domain interactions within KCNQ1 that are affected by KCNE1; dashed purple, KCNQ1 outer vestibule/selectivity filter flexibility; dashed gray, physical proximity and/or interaction without major functional effects. “−” = acidic residue, “+” = basic residue. Citations appear in main text. B. Cartoon of possible orientations with respect to KCNQ1 (blue), based on evidence summarized in panel A, of KCNE1 (upper) and KCNE3 (lower) at resting membrane potential. S6′ = the S6 of an adjoining KCNQ1 α subunit. KCNEs are depicted as semi-transparent to avoid concealing KCNQ1 features.