KCNJ2 Membrane Protein Introduction

Introduction of KCNJ2

In 1993, Kubo firstly cloned the KCNJ2 gene from a macrophage cell line. Inward rectifier potassium channel 2 (KCNJ2), also known as K_ir2.1, is encoded by the KCNJ2 gene. KCNJ2 belongs to the classical inward-rectifier potassium channels (K_ir, IRK) family (K_ir2 subfamily). KCNJ2 is widely expressed in tissues and cell types, including neurons, skeletal muscle, cardiac myocytes, immune system, and carcinoma cells, conducting a strong inward rectifier K⁺ current. Similar to other members of the K_ir family, KCNJ2 tetramerize to form functional inwardly rectifying channels, and each monomer contains two transmembrane helix domains (M1 and M2), an ion-selective P-loop between M1 and M2, and cytoplasmic N- and C-terminal domains. In the heart, KCNJ2 can form the cardiac inward rectifier K⁺ channels combined with Kir2.2, 2.3 and 2.4 to drive the transmembrane potassium current I_k1, which is an important repolarizing current contributing to the terminal phase of the cardiac action potential and has a key role in the stabilization of the resting membrane potential.

Function of KCNJ2 Membrane Protein

With a greater tendency for K⁺ uptake than K⁺ export, KCNJ2 plays an essential role in maintaining the resting membrane potential and regulating cellular excitability in small-cell lung cancer (SCLC) cells, cardiac myocytes, skeletal muscle, and neurons. The aberrant KCNJ2 expression, missense mutations, small deletions, insertions or nonsense mutations can change the K⁺ channels expression levels, substantially affects the cellular processes such as cell death, apoptosis, proliferation, and adhesion, which is linked to a variety of cardiac and neurological disorders. It is documented that KCNJ2 mutations are associated with Andersen-Tawil syndrome (ATS1), also denoted as long QT syndrome type 7 (LQT7), short QT syndrome (SQT3), familial atrial fibrillation (FAF) and catecholaminergic polymorphic ventricular tachycardia 3 (CPVT3). For example, the KCNJ2 mutation R82W, V227F, R67W, C101R, G144D, T305S and R260P, all are related to a clinical phenotype of CPVT, while G215D, V302M are associated with ATS1. Moreover, overexpression of KCNJ2 is correlated with the clinical stage and chemotherapy response in SCLC patients and heterozygous deletion of the entire KCNJ2 gene causes of sudden cardiac death.

Fig.1 Topology of Kir2.1 channel showing Andersen-Tawil syndrome (ATS)-related mutation sites. (Kimura, 2012)

Application of KCNJ2 Membrane Protein in Literature

1. Kalscheur M.M., et al. KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia. Heart rhythm. 2014, 11(5): 885-894. PubMed ID: 24561538
   
   

   In this article, using the whole-cell voltage clamp technique, the authors evaluated that R67Q-Kir2.1 was associated with an adrenergic-dependent clinical and cellular phenotype with increased calcium enhanced rectification abnormality.

2. Liu H., et al. Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway. Molecular cancer. 2015, 14(1): 59. PubMed ID: 25880778
   
   

   This article reported that KCNJ2 was simultaneously regulated by the Ras/MAPK pathway and miR-7, and it can modulate cell growth and drug resistance by regulating MRP1/ABCC1 expression. Using KCNJ2 shRNA to inhibit KCNJ2 expression would impair cell growth and sensitized the cancer cells to chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest.

3. Ördög B., et al. Identification and functional characterisation of a novel KCNJ2 mutation, Val302del, causing Andersen-Tawil syndrome. Canadian journal of physiology and pharmacology. 2015, 93(7): 569-575. PubMed ID: 26103554
   
   

   The authors identified and analyzed the function of a novel KCNJ2 mutation, Val302del in a patient with ATS. Cells transfected with Val302del Kir2.1 subunit cannot be detected current, while transfected with the WT allele displayed a robust current with strong inward rectification. They deduced that the mutation affects potassium conductivity and (or) gating of the WT/Val302del heteromeric Kir2.1 channel.

4. Deo M., et al. KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia. Proceedings of the National Academy of Sciences. 2013, 201218154. PubMed ID: 23440193
   
   

   This article revealed a de novo mutation (E299V) was the result of A896T substitution in a highly conserved region of KCNJ2, which resulted in atrial fibrillation and ventricular proarrhythmia in addition to the short QT syndrome 3.

5. Munoz C., et al. Up-regulation of Kir2.1 (KCNJ2) by the serum & glucocorticoid inducible SGK3. Cellular Physiology and Biochemistry. 2014, 33(2): 491-500. PubMed ID: 24556932
   
   

   The authors found that injection of 10 ng cRNA encoding wild-type SGK3 and (S419D) SGK3 into Xenopus oocytes can significantly enhance Kir2.1-mediated currents, while SGK inhibitor EMD638683 would restrain this process. So, it was deduced that SGK3 was a novel regulator of Kir2.1.

KCNJ2 Preparation Options

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Reference

1. Kimura H, et al. (2012). Phenotype variability in patients carrying KCNJ2 mutations. Circulation: Genomic and Precision Medicine. CIRCGENETICS. 111.962316.

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