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The KCNE family is a group of small, non-conducting, single transmembrane domain proteins known to modulate certain voltage-gated potassium channels. KCNE4 is a membrane protein belonging to a single transmembrane domain protein family, which is known to have significant effects on the control of certain potassium channels.
KCNE4 regulates Kv α subunits
KCNQ1 is a six transmembrane domain voltage-gated K+ channel which plays an important role in controlling the potassium current in several tissues. KCNQ1 mRNA has been found in heart, liver, kidney, lungs, thymus, gastro-intestinal organs, salivary glands, ocrine pancreas and stria vascularis in the cochlea. The expression of KCNQ1 induces voltage dependence, slow activation and slow inactivation of outgoing potassium currents.
The co-expression of KCNQ1 and KCNE4 completely inhibited the current of KCNQ1 in Xenopus oocytes. This was reproduced in mammalian CHO-K1 cells. The delayed mRNA coding of KCNE4 in oocytes expressing KCNQ1 suggested that KCNE4 had an effect on the KCNQ1 channel already expressed in the plasma membrane. Furthermore, it has been found that KCNE4 does not alter the currents generated by KCNQ2–5 or hERG1 channels.
Various effects have been discovered for KCNE4 on Kv1 (KCNA) subfamily delayed rectifier channels. In Xenopus oocytes and HEK cells, mouse KCNE4 strongly inhibited Kv1.1 (KCNA1), a channel best known for neuronal functions but also expressed in the heart and Kv1.3 (KCNA3), a channel important in lymphocytes.
KCNE4 not only modulates KCNQ1, but also regulates Kv4.3, the major α subunit generating Ito in human ventricles, which is encoded by a gene (KCND3) associated with Brugada, sudden infant death syndrome, autopsy-negative sudden unexplained death, and early-onset persistent lone atrial fibrillation.
KCNE4 is much more highly expressed in male versus female mouse heart. It arises from positive regulation of KCNE4 expression by 5α-dihydrotestosterone (DHT); castrated males showed similar left ventricular KCNE4 expression to that of young adult females, while this could be reversed by implantation of slow-release DHT pellets at the time of castration. In male mouse ventricular myocytes, KCNE4 deletion specifically reduced the magnitude of the fast transient outward current (Ito,f), which is generated by Kv4.2 and possibly also Kv4.3, and the slowly activating Kv current IK, which is generated by Kv1.5 in mice.
Functions for KCNE4 outside the heart
KCNE4 regulates the Ca2+-activated K+ channel, BK. KCNE4 is localized, in rat kidney, to apical membranes of intercalated cells in the medulla and the renal cortex, where it co-localizes with BK channel α subunits. BK channels regulate flow-dependent K+ secretion in rabbit kidney, where BK expression is down-regulated by a low K+ diet.
KCNE4 also regulates the KCNQ4 α subunit in vivo, in mesenteric arteries. KCNE4 was found to be the predominant KCNE transcript in rat arteries, and it co-localizes with KCNQ4 in rat mesenteric artery. Human KCNE4S was found to augment KCNQ4 activity, in HEK cells and in Xenopus oocytes. Morpholino-mediated knockdown of KCNE4 in rat mesenteric artery reduced surface expression of KCNQ4, depolarized the arterial myocytes, and reduced sensitivity of arterial tone to KCNQ family modulators, all consistent with a role for KCNQ4-KCNE4 channels in this tissue. KCNE4 knockdown also increased sensitivity to vasoconstricting drugs, supporting a role for KCNE4-containing channels in regulating arterial tone.