KCNE3 Membrane Protein Introduction

Introduction of KCNE3

KCNE3, also known as potassium voltage-gated channel subfamily E regulatory subunit 3, potassium channel, voltage gated subfamily E regulatory beta subunit 3, potassium voltage-gated channel, Isk-related family, member 3, cardiac voltage-gated potassium channel accessory subunit, voltage-gated K+ channel subunit MIRP2, HOKPP, MiRP2, or HYPP, is a single-span integral membrane protein with 103 amino acids length. In humans, it is encoded by the KCNE3 gene located on the chromosome 11q13.4. The KCNE3 gene codes for the protein Isk-related family member 3 that is a beta subunit of the potassium voltage-gated channel. It is most predominantly detectable in the colon, small intestine, and some specific stomachic cells. It also presents in the kidney and trachea, and with lower levels in the brain, heart and skeletal muscle in certain species.

Function of KCNE3 Membrane Protein

KCNE3 is a widely expressed type I membrane protein that is believed to modulate the gating kinetics and enhance the stability of channel complexes. It regulates the function and trafficking of some voltage-gated potassium (Kv) channels, including KCNQ1, KCNQ4, Kv2.1, Kv3.1, Kv3.2, and hERG. In intestinal and tracheal epithelia, KCNE3-KCNQ1 complexes play a key role in potassium ion recycling, which is required for the secretion of transepithelial chloride ion. Further, it has abilities to convert KCNQ1 into a voltage-independent and constitutively active “leak” channel. It has been reported that KCNE3 implicates in disorders associated with the salt and fluid homeostasis, for example, cystic fibrosis (CF). In addition, KCNE3 can assemble with KCNB1 that modulates the gating features of the delayed rectifier Kv channel KCNB1. Mutations in the human KCNE3 have been correlated with the Brugada syndrome and hypokalemic periodic paralysis. KCNE3-linked Brugada syndrome is thought to arise since KCNE3 mutant is unable to restrain Kv4.3 channels in ventricular myocytes. Additionally, several pieces of evidence suggested KCNE3 may be related to the Ménière’s disease in Japanese.

Fig.1 Structure of KCNE3 in a bilayer membrane. (Kroncke, 2016)

Application of KCNE3 Membrane Protein in Literature

1. Julio-Kalajzić F., et al. K2P TASK-2 and KCNQ1-KCNE3 K⁺ channels are major players contributing to intestinal anion and fluid secretion. J Physiol. 2018, 596(3): 393-407. PubMed ID: 29143340
   
   

   The article concluded that KCNQ1-KCNE3 and TASK-2 played major parts in the intestinal anion and fluid secretory phenotype. The persistence of an admittedly decreased secretory activity in the absence of two conductance suggested that further additional K+ channels as yet unidentified benefit to the robustness of intestinal anion secretory processes.

2. Barro-Soria R., et al. KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proc Natl Acad Sci U S A. 2017, 114(35): E7367-E7376. PubMed ID: 28808020
   
   

   The voltage clamp fluorometry was used to determine how KCNE1 and KCNE3 influenced the gate of KCNQ1 and the voltage sensor. By separating S4 movement and gate opening, the findings revealed that KCNE1 affected both the S4 movement and the gate, while KCNE3 impacted on the S4 movement and only affected the gate in KCNQ1 if an intact S4-to-gate coupling was showed.

3. King E.C., et al. Targeted deletion of Kcne3 impairs skeletal muscle function in mice. FASEB J. 2017, 31(7): 2937-2947. PubMed ID: 28356343
   
   

   KCNE3 was the first reported skeletal muscle K⁺ channel disease gene and could form heteromeric voltage-gated K+ channels with the skeletal muscle-expressed KCNC4 α subunit. Here, this report confirmed the KCNE3 transcript as well as protein expression in mouse skeletal muscle by using Kcne3^-/- tissue as a negative control.

4. Abbott G.W. KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene. 2016, 576(1 Pt 1): 1-13. PubMed ID: 26410412
   
   

   The human KCNE gene family contained five genes coding for single transmembrane-spanning ion channel regulatory subunits. The main function of KCNE subunits appeared to regulate voltage-gated potassium (Kv) channels. The paper primarily reviewed the frequently opposite effects of KCNE1 and KCNE3 on Kv channel biology, particularly on the regulation of KCNQ1.

5. Al-Hazza A., et al. Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis. Biochem Biophys Res Commun. 2016, 470(2): 473-478. PubMed ID: 26718405
   
   

   KCNQ1/KCNE3 channels only contributed a little to basolateral conductance in normal colonic crypts, with elevated channel activity in ulcerative colitis (UC) showing insufficient to prevent colonic cell depolarization in this disease. That supported a proposal that defective Na(+) absorption rather than intensive Cl(-) secretion is the major mechanism of diarrhea in UC.

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Reference

1. Kroncke B M, et al. (2016). Structural basis for KCNE3 modulation of potassium recycling in epithelia. Sci Adv. 2(9): e1501228.

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