KCNE4 Membrane Protein Introduction

Introduction of KCNE4

KCNE4, also known as MIRP3, cardiac voltage-gated potassium channel accessory subunit 4, potassium voltage-gated channel subfamily E regulatory subunit 4, potassium channel, voltage gated subfamily E regulatory beta subunit 4, or potassium voltage-gated channel, Isk-related family, member 4, is a transport protein of about 23.8 k Da, and is composed of 678 amino acids length. In humans, it is encoded by the KCNE4 gene which is mapping to the chromosome 2q36.1. The KCNE4 gene contains 4 exons and has a typical single membrane-spanning domain at its N-terminus, a characteristic protein kinase C (PKC) phosphorylation site following the transmembrane region, and an intracellular C-terminus. A longer form of KCNE4 protein, termed as KCNE4L, was discovered in 2016, and its human transcript is most highly expressed in uteri.

Function of KCNE4 Membrane Protein

The voltage-dependent potassium (Kv) channel comprises four pore-forming alpha subunits that sense and respond to voltage change and mediate ion permeation. KCNE4, as a KCNE accessory subunit, is a small, single transmembrane protein that interacts with and modulates the activity of Kv channel. Interestingly, despite KCNE4 being recognizably by far the highest expressed KCNE subunit in human heart, its disease connection is limited to a single polymorphism related to the atrial fibrillation. KCNE4 is best known for regulating the KCNQ1 Kv α subunit. It can strongly suppress the KCNQ1 potassium channel, which is acknowledged to play essential roles in human cardiac myocyte repolarization, and in multiple epithelial cells. Also, KCNE4 is able to modulate KCNQ4, Kv1.x, Kv2.1, Kv4.x and BK (Ca2+-activated potassium) α subunits in heterologous co-expression assays or in vivo. It usually functions as an inhibitory subunit to inhibit Kv channel, but this varies relying on the channel subtype.

Fig.1 Cartoon of KCNE4 subunits in a K_vα-KCNE4 channel complex, with a hypothetical 4:2 stoichiometry. (Crump, 2016)

Application of KCNE4 Membrane Protein in Literature

1. Hu Z., et al. Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice. Sci Rep. 2018, 8(1): 8258. PubMed ID: 29844497
   
   

   The results demonstrated for the first time that male sex predisposed in aged mice to risky ventricular tachyarrhythmias despite sex-independent electrical and ischemic substrates, due to the testosterone-dependent impairment of RISK/SAFE pathway induction.

2. Abbott G.W. KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis. Gene. 2016, 593(2): 249-260. PubMed ID: 27484720
   
   

   KCNE proteins as single transmembrane-segment voltage-gated potassium (Kv) channel ancillary subunits exhibited a broad range of physiological functions. This report covered current knowledge regarding molecular mechanisms of KCNE4 and KCNE5 functions, human disease associations, and findings from very current studies of cardiovascular pathophysiology in Kcne4(-/-) mice.

3. Crump S.M., et al. Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice. FASEB J. 2017, 30(1): 360-369. PubMed ID: 26399785
   
   

   The capacity of myocardial repolarization changed with sex, age, and pathology, whereas the molecular bases for these variations were incompletely understood. Here, KCNE4 was shown to be a 5α-dihydrotestosterone (DHT)-regulated determinant of cardiac excitability and considered as a molecular substrate for sex- and age-dependent cardiac arrhythmogenesis.

4. Abbott G.W and Jepps T.A. Kcne4 deletion sex-dependently alters vascular reactivity. J Vasc Res. 2016, 53(3-4): 138-148. PubMed ID: 27710966
   
   

   These findings confirmed an important role for KCNE4 in the regulation of Kv7 channel activity to regulate vascular tone and provided the first known molecular mechanism for sex-specificity of this regulation that had significant implications for vascular reactivity and probably underlies sex-specific susceptibility to cardiovascular diseases.

5. Solé L., et al. The C-terminal domain of Kv1.3 regulates functional interactions with the KCNE4 subunit. J Cell Sci. 2016, 129(22): 4265-4277. PubMed ID: 27802162
   
   

   The results in this paper suggested that the tertiary structure of the C-terminal domain of Kv1.3 was required and sufficient for the interaction of Kv1.3-KCNE4. But this part was apparently not implicated in modulating the Kv1.3 gating. Moreover, the KCNE4-dependent intracellular retention of the channel, negatively affecting the activity of Kv1.3, was mediated by two independent mechanisms.

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Reference

1. Crump S M, et al. (2016). Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice. FASEB J. 30(1): 360-369.

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