KCNE4

2370457814ENSG00000152049ENSMUSG00000047330Q8WWG9Q9WTW3NM_080671NM_021342NP_542402NP_067317Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene. Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene. Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. The KCNE4 gene encodes KCNE4 (originally named MinK-related peptide 3 or MiRP3), a member of the KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits. KCNE4 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates KCNQ4, Kv1.x, Kv2.1, Kv4.x and BK α subunits in heterologous co-expression experiments and/or in vivo. KCNE4 often, but not always, acts as an inhibitory subunit to suppress potassium channel function, but this varies depending on the channel subtype. KCNE4 strongly inhibits the KCNQ1 potassium channel, which is known to play important roles in human cardiac myocyte repolarization, and in multiple epithelial cell types. KCNE4 inhibition of KCNQ1 requires calmodulin, which binds to both KCNQ1 and KCNE4. KCNE4 can also inhibit complexes formed by KCNQ1 and KCNE1. KCNE4 has no known effect on KCNQ2, KCNQ3 or KCNQ5 channels, but augments activity of KCNQ4 in HEK cells, mesenteric artery and Xenopus laevis oocytes. KCNE4 strongly inhibits Kv1.1 and Kv1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving Kv1.2 and Kv1.4 currents unaffected. KCNE4 augments Kv1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to Kv1.5, in ventricular myocytes. KCNE4 inhibited Kv2.1 currents by 90% but had little to no effect on currents generated by heteromers of Kv2.1 with the regulatory α subunit Kv6.4. KCNE4 slows activation and inactivation of Kv4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with Kv4.2 and KCNE4. Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by Kv4.2. Although mouse KCNE4 reportedly had no effect on Kv4.3 when coexpressed in oocytes, human KCNE4 was found to accelerate inactivation and recovery from inactivation of Kv4.3-KChIP2 complexes. KCNE4 has also been found to regulate the large-conductance Ca2+-activated potassium channel, BK. KCNE4 inhibits BK activity by positive-shifting the voltage dependence of BK activation and accelerating BK protein degradation.