KCNE1 and KCNE3 β-Subunits Regulate Membrane Surface Expression of Kv12.2 K+ Channels In Vitro and Form a Tripartite Complex In Vivo

Clancy, Sinead M.; Chen, Bihan; Bertaso, Federica; Mamet, Julien; Jegla, Timothy

doi:10.1371/journal.pone.0006330

Cited by 16 publications

(20 citation statements)

References 43 publications

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“…Although the cardiac function of KCNE1 has been mostly explored in previous studies, studies demonstrated that KCNE1 is also expressed in neuronal cells and regulates a neuronal K v channel function (18, 37). Because BACE1 is expressed at high levels in neurons as compared to other cell types (38), BACE1 may have more profound roles in regulating neuronal KCNE1‐and KCNE1‐regulated K v channels in neuronal cells under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

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BACE1 and presenilin/γ‐secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage‐gated potassium channels

et al. 2013

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BACE1 and presenilin (PS)/γ-secretase play a major role in Alzheimer's disease pathogenesis by regulating amyloid-β peptide generation. We recently showed that these secretases also regulate the processing of voltage-gated sodium channel auxiliary β-subunits and thereby modulate membrane excitability. Here, we report that KCNE1 and KCNE2, auxiliary subunits of voltage-gated potassium channels, undergo sequential cleavage mediated by either α-secretase and PS/γ-secretase or BACE1 and PS/γ-secretase in cells. Elevated α-secretase or BACE1 activities increased C-terminal fragment (CTF) levels of KCNE1 and 2 in human embryonic kidney (HEK293T) and rat neuroblastoma (B104) cells. KCNE-CTFs were then further processed by PS/γ-secretase to KCNE intracellular domains. These KCNE cleavages were specifically blocked by chemical inhibitors of the secretases in the same cell models. We also verified our results in mouse cardiomyocytes and cultured primary neurons. Endogenous KCNE1- and KCNE2-CTF levels increased by 2- to 4-fold on PS/γ-secretase inhibition or BACE1 overexpression in these cells. Furthermore, the elevated BACE1 activity increased KCNE1 processing and shifted KCNE1/KCNQ1 channel activation curve to more positive potentials in HEK cells. KCNE1/KCNQ1 channel is a cardiac potassium channel complex, and the positive shift would lead to a decrease in membrane repolarization during cardiac action potential. Together, these results clearly showed that KCNE1 and KCNE2 cleavages are regulated by BACE1 and PS/γ-secretase activities under physiological conditions. Our results also suggest a functional role of KCNE cleavage in regulating voltage-gated potassium channels.

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Section: Discussionmentioning

confidence: 99%

“…7). In addition to KCNE2, studies showed regulatory roles of other KCNEs on neuronal Kv channels, including KCNE1 and KCNE3 (18, 37, 42, 43). Therefore, it will be very interesting to explore whether BACE1 and/or PS/γ‐secretase cleave these KCNEs and regulate neuronal Kv channels, as well as KCNE2.…”

Section: Discussionmentioning

confidence: 99%

BACE1 and presenilin/γ‐secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage‐gated potassium channels

et al. 2013

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“…Kv12.2 may, thus, also need a ␤-subunit for efficient glycosylation and cell surface expression. Another possibility is that, as a recent study showed using Xenopus oocytes (41), intrinsic KCNE1 and KCNE3 may down-regulate the cell surface expression of Kv12.2 in CHO cells.…”

Section: Discussionmentioning

confidence: 99%

Triple N-Glycosylation in the Long S5-P Loop Regulates the Activation and Trafficking of the Kv12.2 Potassium Channel

Noma

Kimura

Minatohara

et al. 2009

Journal of Biological Chemistry

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Mammalian voltage-dependent potassium (Kv) channels regulate the excitability of nerve and muscle cells. Kv12.2 features the longest S5-P loop among all known mammalian Kv channels with the most N-linked glycosylation sites (three sites). Despite its unique structural features, Kv12.2 is not well characterized. Because glycosylation plays important roles in the folding, trafficking, and function of various Kv channels, we focused on the N-glycosylation of Kv12.2. We show that Kv12.2 is N-glycosylated in Chinese hamster ovary (CHO) cells and in cultured neurons as well as in the mouse brain. As an effect of N-glycosylation on the function of Kv12.2, we demonstrate that removal of sugar chains causes a depolarizing shift in the steady-state activation without a significant reduction in current amplitude. Unlike the previously reported shift for Shaker-type Kv channels, this shift does not appear to be due to negatively charged sialic acid residues in the sugar chains. We next examined the trafficking in CHO cells to address whether the unglycosylated Kv12.2 channels are utilized in vivo. Although double mutants, retaining only one glycosylation site, are trafficked to the surface of CHO cells irrespective of the position of the glycosylated site, unglycosylated channels are not trafficked to the cell surface. Furthermore, we could not detect unglycosylated channels in the mouse brain. Our data suggest that only glycosylated Kv12.2 channels show proper voltage dependence and are utilized in vivo.

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“…In contrast, KCNE3 strongly inhibits hERG, again by an unresolved mechanism 17 , although the same KCNE3 substitution (R83H) that disrupts ability to constitutively open KCNQ1 channels and augment Kv3.4 currents 65 also blunts the ability of KCNE3 to inhibit hERG 66 . Interestingly, KCNE1 and KCNE3 are reported to form tripartite complexes with Kv12.2 (also termed ELK2 or KCNH3), inhibiting its surface expression and activation in Xenopus oocytes; this may also occur in mouse brain 67 .…”

Section: Kcne1 and Kcne3 Regulation Of Other Kv α Subunitsmentioning

confidence: 99%

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

Abbott

2016

Gene

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The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE genes 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 an invaluable tool 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.

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KCNE1 and KCNE3 β-Subunits Regulate Membrane Surface Expression of Kv12.2 K+ Channels In Vitro and Form a Tripartite Complex In Vivo

Cited by 16 publications

References 43 publications

BACE1 and presenilin/γ‐secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage‐gated potassium channels

BACE1 and presenilin/γ‐secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage‐gated potassium channels

Triple N-Glycosylation in the Long S5-P Loop Regulates the Activation and Trafficking of the Kv12.2 Potassium Channel

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

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