KCNJ8 Membrane Protein Introduction

Introduction of KCNJ8

ATP-sensitive inward rectifier potassium channel 8 (KCNJ8), also known as K_ir6.1, is encoded by the KCNJ8 gene. KCNJ8 normally assembles with KCNJ11 and two regulatory sulfonylurea receptors (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively) to form ATP-sensitive potassium (K_ATP) channels, which can couple the metabolic state of the cell with its electrical activity and hence contractility in multiple tissues. The architecture of KCNJ8 is similar to other members of K_ir family, sharing two putative membrane-spanning domains (M1 and M2) and form a tetrameric complex linked by an extracellular pore-forming region and cytoplasmic N- and C-terminal domains. Aided by the screening of a somatic cell mapping panel and fluorescent in situ hybridization, the gene KCNJ8 is mapped to chromosome 12p12.1. KCNJ8 is widely expressed in different tissues and cells, significantly in cardiomyocytes, pancreatic and neuronal tissues.

Function of KCNJ8 Membrane Protein

As a component of K_ir6.1 (K_ATP) channel, KCNJ8 critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, such as sepsis, corresponding with the premature sudden death in KCNJ8-deficient mice. In the brain, KCNJ8 participates in the formation of mitochondrial ATP-sensitive potassium channel (mitoKATP), which was involved in Parkinson’s disease (PD) mainly via the regulation of mitochondrial biogenesis and fission/fusion. So KCNJ8 is recognized as a key contributor in the interaction with mitochondrial dynamics in dopamine neurodegeneration. Significantly, a hotspot mutation of KCNJ8 (S422L) has been extensively studied in recent decades. It is reported that S422L mutation has a susceptible link to J wave syndrome (JWS), Cantú syndrome (CS), atrial fibrillation (AF), and sudden infant death syndrome (SIDS). In vitro functional expression studies indicated that the function of ATP-sensitive potassium (K_ATP) channel current (I_K-ATP) is increased with reduced sensitivity to ATP in S422L mutation samples. Moreover, two loss-of-function KCNJ8 mutations (E332del and V346I) has been acknowledged as a novel pathogenic mechanism in sudden infant death syndrome (SIDS).

Fig.1 Molecular characterization of SIDS-associated KCNJ8-encoded Kir6.1 K_ATP channel mutations. (Tester, 2011)

Application of KCNJ8 Membrane Protein in Literature

1. Cooper P.E., et al. Cantú Syndrome Resulting from Activating Mutation in the KCNJ8 Gene. Human mutation. 2014, 35(7): 809-813. PubMed ID: 24700710
   
   

   In this article, the authors screened KCNJ8 in a Cantú syndrome patient, whose gene ABCC9 (regulatory sulfonylurea receptor2, SUR2) mutation was negative and identified a de novo missense mutation encoding Kir6.1 channels [p.Cys176Ser], which showed markedly higher activity than wild-type channels.

2. Tester D.J., et al. Loss-of-function mutations in the KCNJ8-encoded Kir6. 1 K_ATP channel and sudden infant death syndrome. Circulation: Genomic and Precision Medicine. 2011, 4(5): 510-515. PubMed ID: 21836131
   
   

   This article provided molecular and functional evidence implicated loss-of-function KCNJ8 mutations (E332del and V346I) as a novel pathogenic mechanism in sudden infant death syndrome (SIDS), possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors similar to the mouse models of KCNJ8 deficiency.

3. Barajas-Martínez H., et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm. 2012, 9(4): 548-555. PubMed ID: 22056721
   
   

   This article reported the identification of an S422L-KCNJ8 mutation in early repolarization syndrome (ERS) and Brugada syndrome (BrS) and pointed to S422L as a possible hotspot mutation.

4. Veeramah K.R., et al. The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. European Journal of Human Genetics. 2014, 22(1): 94. PubMed ID: 23632791
   
   

   The authors found that the S422L mutation was at a significantly higher frequency in Ashkenazi Jews (~4%), compared with other populations, which had increased risk of J-wave syndromes and ultimately sudden cardiac death.

5. Delaney J.T., et al. A KCNJ8 mutation associated with early repolarization and atrial fibrillation. Europace. 2012, 14(10): 1428-1432. PubMed ID: 22562657
   
   

   The authors revealed that KCNJ8-S422L mutation was associated with increased susceptibility of atrial fibrillation (AF) and early repolarization (ER).

KCNJ8 Preparation Options

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Reference

1. Tester D J, et al. (2011). Loss-of-function mutations in the KCNJ8-encoded Kir6. 1 K_ATP channel and sudden infant death syndrome. Circulation: Genomic and Precision Medicine. 4(5): 510–515.

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