KCNJ6 Membrane Protein Introduction

Introduction of KCNJ6

G protein-activated inward rectifier potassium channel 2 (GIRK2), also known as KCNJ6, K_ir3.2, KATP2, or KCNJ7, is a type of G protein-gated ion channel and is encoded by the KCNJ6 gene. KCNJ6 is one of four identified K_ir3 channels, which normally associates with KCNJ3 or KCNJ5 to form various G-protein-activated heteromultimer pore-forming units in different tissues and cell types, corresponding to their diverse functional roles. Sharing similar crystal structure with other members of the K_ir family, KCNJ6 consists of two transmembrane helix domains (M1 and M2), a pore loop between M1 and M2, and cytoplasmic N- and C-terminal domains. With a greater tendency to allow potassium to flow into cells rather than out of cells, KCNJ6 plays an important role in setting the resting membrane potential and regulation of cellular excitability. Aided by the screening of a somatic cell mapping panel and fluorescent in situ hybridization, the gene KCNJ6 is mapped to chromosome 21 (21q22.1-22.2).

Function of KCNJ6 Membrane Protein

KCNJ6 is recognized as a putative subunit of human ATP-sensitive K-channel, which is best studied in the pancreatic β-cells where it plays a central role in insulin release in response to nutrients. Along with the development of research, it is reported that KCNJ6 is also expressed in brain (especially in the CNS, mainly at postsynaptic sites) and combines with KCNJ3 (GIRK1) to form neuronal GIRK channels, which are related to hyperalgesia, seizure susceptibility, cognitive functions, reward mechanisms, and anxiety. The corticotrophin-releasing hormone (CRH) can enhance the suppression of postsynaptic currents mediated by KCNJ6 channels in D2-dopaminergic neurons in mice. KCNJ6 expression can be regulated by corticosterone, providing evidence that KCNJ6 interacts with neuronal stress systems. So, KCNJ6 may be a linker of brain stress systems, dopaminergic signaling, and thus reinforcement-related behavior. It is documented that KCNJ6 is associated with the reinforcing and/or aversive motivational aspects of ethanol action and nicotine addiction. Moreover, several animal studies showed that KCNJ6 can influence pain and opioid analgesic responses. Genetic variants in KCNJ6 will cause various diseases, such as IS-like seizures, Down syndrome (DS) and Keppen-Lubinsky syndrome (KPLBS).

Fig.1 The Crystal structure of KCNJ6 and KCNJ6 mutation. (Masotti, 2015)

Application of KCNJ6 Membrane Protein in Literature

1. Masotti A., et al. Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. The American Journal of Human Genetics. 2015, 96(2): 295-300. PubMed ID: 25620207
   
   

   In this article, the authors sequenced the exomes of three unrelated individuals affected by KPLBS and found the heterozygous mutations in KCNJ6 may be responsible for this rare disease. Their results established KPLBS as a channelopathy and suggested that KCNJ6 had the potency to be a candidate gene for other lipodystrophies.

2. Bruehl S., et al. Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes. PAIN. 2013, 154(12): 2853-2859. PubMed ID: 23994450
   
   

   This article used a tag SNP approach to test pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation and verified that variations in the KCNJ6 gene would influence both acute and chronic human pain responses.

3. Nishizawa D., et al. Association between KCNJ6 (GIRK2) gene polymorphism rs2835859 and post-operative analgesia, pain sensitivity, and nicotine dependence. Journal of pharmacological sciences. 2014, 126(3): 253-263. PubMed ID: 25346042
   
   

   This article investigated the contribution of genetic variations of the KCNJ6 (GIRK2) to individual differences in the sensitivity to opioid analgesia and found that polymorphism rs2835859 was associated with sensitivity to both cold and mechanical pain, post-operative analgesia, susceptibility to nicotine dependence, and successful smoking cessation.

4. Cooper A., et al. Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. Proceedings of the National Academy of Sciences. 2012, 109(7): 2642-2647. PubMed ID: 22308328
   
   

   The authors used transgenic mice harboring a single trisomy of the Kcnj6 gene to test the behaviors and cellular physiology properties and they revealed that Kcnj6 triploid mice exhibited deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and had accentuated long-term synaptic depression.

5. Clarke T.K., et al. KCNJ6 is associated with adult alcohol dependence and involved in gene× early life stress interactions in adolescent alcohol drinking. Neuropsychopharmacology. 2011, 36(6): 1142. PubMed ID: 21307845
   
   

   The authors examined the role of KCNJ6 polymorphisms in alcohol abuse and dependence population and identified KCNJ6 was associated with alcohol dependence and moderated the effect of early psychosocial stress on risky alcohol drinking in adolescents.

KCNJ6 Preparation Options

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Reference

1. Masotti A, et al. (2015). Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. The American Journal of Human Genetics. 96(2): 295-300.

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