KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis

Abstract

KCNE proteins are single transmembrane-segment voltage-gated potassium (Kv) channel ancillary subunits that exhibit a diverse range of physiological functions. Human KCNE gene mutations are associated with various pathophysiological states, most notably cardiac arrhythmias. Of the five isoforms in the human KCNE gene family, KCNE4 and the X-linked KCNE5 are, to date, the least-studied. Recently, however, interest in these neglected genes has been stoked by their putative association with debilitating or lethal cardiac arrhythmias. The sometimes-overlapping functional effects of KCNE4 and KCNE5 vary depending on both their Kv α subunit partner and on other ancillary subunits within the channel complex, but mostly fall into two contrasting categories - either inhibition, or fine-tuning of gating kinetics. This review covers current knowledge regarding the molecular mechanisms of KCNE4 and KCNE5 function, human disease associations, and findings from very recent studies of cardiovascular pathophysiology in Kcne4(-/-) mice.

Keywords: AMME contiguous gene syndrome; Atrial fibrillation; Brugada syndrome; Cardiac arrhythmia; KCNQ1; Long QT syndrome; Potassium channel.

Figure 1. Topology and primary structures of KCNE4 and KCNE5

(A) Sequence alignment (using EMBL EBI MUSCLE, with display order indicative of closest sequence identities) of the human KCNE family with newly-discovered exon 1-encoded portions of KCNE3 and KCNE4 underlined, and predicted single transmembrane segment of each highlighted with yellow background. Pale blue background: KCNE4 and KCNE5 residues substituted by putative arrhythmia-associated gene variants; gray background: calmodulin binding motif of KCNE4. (B) Cartoon of proposed positioning and stoichiometry of KCNE subunits within a Kv channel complex also containing a tetramer of α subunits. (C) Phylogenetic trees of KCNE4 (left) and KCNE5 (right) proteins constructed using predicted protein sequences from the US National Center for Biotechnology Information database and the ClustalW2 Phylogeny tool (http://www.ebi.ac.uk/Tools/phylogeny/clustalw2_phylogeny/). Numbers indicate branch length and represent relative change over evolutionary time. Gecko = Japanese gecko (Gekko japonicas); lizard = Carolina anole (Anolis carolinensis); hedgehog = European hedgehog (Erinaceus europaeus); rabbit = European rabbit (Oryctolagus cuniculus). Frog = Xenopus tropicalis (KCNE4) or Xenopus laevis (KCNE5).

Figure 2. Currents underlying the ventricular myocyte action potential

(A) Representation of membrane potential (E_m) versus time during an idealized human ventricular myocyte action potential, showing the currents (I) that shape it: I_Na, voltage-gated sodium current; I_to, transient outward potassium current; I_Ca, calcium current; I_K, potassium current; I_Ks, slowly activating potassium current; I_Kr, rapidly activating potassium current; I_K1, inward rectifier potassium current. (B) Body-surface electrocardiogram showing the onset of atrial depolarization (beginning of P wave) to the termination of ventricular repolarization (end of T wave), the QRS complex and the QT interval.

Figure 3. Functional effects of KCNE4 on KCNQ1

(A, B) Example traces and (C, D) mean current-Voltage relationships recorded by two-electrode voltage clamp from oocytes injected with cRNA encoding KCNQ1 (Q1) alone or with KCNE4S (E4). The currents were elicited by 2-second duration steps to potentials between −100 mV and +60 mV, in 20 mV increments, from a holding potential of −80 mV. Reproduced with permission from John Wiley and Sons.

Figure 4. Functional effects of KCNE5 on KCNQ1

(A–D) Example traces and (E) mean current-Voltage relationships recorded by whole-cell patch clamp from cells expressing KCNQ1 (Q1) alone or with KCNE5 (E5) or KCNE1 (E1). The currents were elicited by 3-second duration steps to potentials between −60 mV and +100 mV, in 20 mV increments, from a holding potential of −80 mV (as shown in Voltage protocol to the right of the trace in panel C). Reproduced with permission from Elsevier.

Figure 5. Functional effects of KCNE4 and KCNE5 on KCNQ1-KCNE1

(A) Example traces and (B) mean current-Voltage relationships recorded by whole-cell patch clamp from cells expressing KCNQ1+KCNE1 (I_Ks) with EGFP, KCNE4 or KCNE5. The currents were elicited by 2-second duration steps to potentials between −70 mV and +130 mV, in 20 mV increments, from a holding potential of −80 mV (as shown in Voltage protocol in the lower right corner of panel A). Arrows and bold trace indicate the current trace at +50 mV to highlight the inhibition/shifts in Voltage dependence induced by KCNE4 versus KCNE5. Reproduced with permission from Elsevier.