Recombinant Human G protein-activated inward rectifier potassium channel 2 (KCNJ6)
Description
Introduction to Recombinant Human G Protein-Activated Inward Rectifier Potassium Channel 2 (KCNJ6)
Recombinant Human G protein-activated inward rectifier potassium channel 2, encoded by the KCNJ6 gene, is a crucial component of G protein-gated inwardly rectifying potassium channels (GIRKs). These channels play a significant role in regulating cellular excitability by facilitating the influx of potassium ions into cells, thereby reducing excitability. The KCNJ6 protein is particularly important in the nervous system, where it modulates neuronal activity in response to G protein-coupled receptor signaling.
Structure and Function of KCNJ6
KCNJ6, also known as GIRK2, forms heteromeric channels with other GIRK subunits, such as GIRK1 and GIRK3. These channels are activated by the dissociation of Gβγ subunits from G protein complexes, which bind to the channel and enhance its activity. The inward rectification property of GIRK channels, including those containing KCNJ6, is due to the blockage by intracellular ions like magnesium (Mg²⁺) and polyamines, which preferentially allow potassium ions to flow into the cell rather than out .
Clinical Significance and Associated Disorders
Variants in the KCNJ6 gene have been associated with several clinical conditions:
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Keppen-Lubinsky Syndrome: This rare genetic disorder is characterized by severe intellectual disability, developmental delay, and dysmorphic features. Recent studies have identified milder phenotypes associated with KCNJ6 variants, including obsessive-compulsive disorder and exaggerated startle responses .
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Alcohol Use Disorder (AUD): Noncoding variants in KCNJ6 have been linked to increased excitability in neurons, potentially contributing to AUD. Ethanol exposure can modulate this excitability by enhancing GIRK2 expression .
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Persistent Breast Pain: Variations in the KCNJ6 gene have also been associated with persistent breast pain after breast cancer surgery .
Table 1: KCNJ6-Related Disorders and Phenotypes
| Disorder/Phenotype | Key Features | KCNJ6 Variant Impact |
|---|---|---|
| Keppen-Lubinsky Syndrome | Severe intellectual disability, developmental delay, dysmorphic features | Pathogenic variants reduce channel function |
| Milder Phenotypes | Mild intellectual disability, obsessive-compulsive disorder, exaggerated startle responses | Variants may affect channel regulation |
| Alcohol Use Disorder | Increased neuronal excitability | Noncoding variants decrease GIRK2 expression |
| Persistent Breast Pain | Chronic pain after breast cancer surgery | Variations in KCNJ6 gene expression |
Table 2: KCNJ6 Channel Properties
| Property | Description |
|---|---|
| Ion Selectivity | Preferential influx of potassium ions |
| Activation Mechanism | G protein-coupled receptor signaling via Gβγ subunits |
| Inward Rectification | Blocked by intracellular Mg²⁺ and polyamines |
| Tissue Distribution | Primarily in the nervous system |
Product Specs
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Target Background
This potassium channel, KCNJ6 (GIRK2), potentially plays a crucial role in regulating insulin secretion in response to glucose and/or neurotransmitters acting via G-protein-coupled receptors. Inward rectifier potassium channels exhibit a greater influx of potassium ions compared to efflux. Their voltage dependence is modulated by extracellular potassium concentration; increased external potassium shifts the channel activation to more positive voltages. Inward rectification is primarily due to internal magnesium blocking outward current.
- KCNJ6 -1250A and COMT Val alleles predispose preterm newborns to reduced opioid-induced analgesia. PMID: 27027462
- This study demonstrated an additive genotypic effect of KCNJ6 SNPs on ERO theta power during reward processing, increasing significantly across genotypes. PMID: 27993610
- Three of four studied KCNJ6 SNPs showed significant associations with theta event-related oscillations in adults. PMID: 27847216
- This study suggests that KCNJ6 gene variations are associated with both mild and severe persistent breast pain post-breast cancer surgery. PMID: 25599232
- The KCNJ6 (GIRK2) gene polymorphism rs2835859 may serve as a predictor for analgesic sensitivity, pain perception, and nicotine dependence susceptibility. PMID: 25346042
- In a transgenic mouse model, GIRK2 plays a significant role in the development of infantile spasms. PMID: 26032891
- Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. PMID: 25620207
- Three SNPs (rs2835914, rs8129919, rs2836050) within KCNJ6 were associated with preoperative breast pain. PMID: 24392765
- Eight KCNJ6 SNPs demonstrated significant associations with pain-related phenotypes. PMID: 23994450
- Ethanol directly interacts with GIRK channels, enhancing interaction with phosphatidylinositol 4,5-bisphosphate and activating the channel. PMID: 24145411
- A 3.5 Å resolution crystal structure reveals the mammalian GIRK2 channel complexed with βγ G-protein subunits, the central signaling complex linking G-protein-coupled receptor stimulation to K+ channel activity. PMID: 23739333
- KCNJ6 (GIRK2) accounts for some variations in frontal theta band oscillations. PMID: 22554406
- Conformational changes from ligand binding to delta-opioid receptors (DORs) are transmitted to Kir3.1/Kir3.2 channels. PMID: 23175530
- GIRK2 is expressed in nearly all human pigmented neurons and mouse tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and ventral tegmental areas. PMID: 22252428
- GIRK2 overexpression in Ts65Dn mice affects the balance between GABA(A) and GABA(B) inhibition of CA1 pyramidal neurons, potentially contributing to cognitive deficits in this Down syndrome model. PMID: 22178330
- KCNJ6 is associated with alcohol dependence and may moderate the impact of early psychosocial stress on risky alcohol use in adolescents. PMID: 21307845
- The KCNJ6 promoter is activated by Trichostatin A (TSA) treatment and serum depletion, as demonstrated by promoter reporter assays in HEK 293 cells. PMID: 20494980
- A significant interaction was observed between the TT genotype of rs2070995 (KCNJ6) and the GG genotype of rs2253206 (CREB1) on rumination. PMID: 20943350
- Overexpression of the GIRK2 channel subunit and its coupling to GABA(B) receptors may contribute to mental and functional disabilities in Down syndrome. PMID: 20655490
- KCNJ6 (GIRK2) gene polymorphisms influence postoperative analgesic requirements after major abdominal surgery. PMID: 19756153
- L344 and G347 residues play crucial functional roles in G(βγ) activation of GIRK2 channels. PMID: 14724209
- The potential synergistic effects and implications of KIR3.2 and KIR4.2 overexpression in Down's syndrome brain development are discussed. PMID: 15068243
- Reduced GRK2 expression likely results from decreased cAMP stimulation in cold thyroid nodules. PMID: 15772902
- KCNJ6 may play a significant role in altered cardiac regulation in Down syndrome patients. PMID: 18303085
- Kir3.2 interacts with Gβ1-3, but not Gβ4 or Gβ5. These interactions are enhanced by Gγ co-expression and are insensitive to DN Sar1 or Rab1. PMID: 19135528
Q&A
FAQs for Recombinant Human G Protein-Activated Inward Rectifier Potassium Channel 2 (KCNJ6)
Advanced Research Questions
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How do noncoding KCNJ6 variants alter neuronal excitability in disease models?
Studies using iPSC-derived neurons from AUD-affected individuals show: -
What structural features govern ethanol-KCNJ6 interactions?
Key mechanistic insights: -
How can KCNJ6 research inform personalized therapies for addiction disorders?
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Endophenotype targeting: The ERO theta power correlates with KCNJ6 haplotype-dependent excitability .
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Gene editing: CRISPR-Cas9 correction of rs2835859 restores baseline neuronal activity in vitro .
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Small-molecule screens: Compounds mimicking ethanol’s GIRK2 activation (e.g., ML297) show therapeutic potential .
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Methodological Comparison Tables
Table 1: Recombinant KCNJ6 Expression Systems
| System | Yield (µg/mL) | Tag | Functional Validation Method |
|---|---|---|---|
| HEK-293 | 50 | Myc-DYKDDDDK | Electrophysiology, WB |
| E. coli | 20 | GST/His | Ligand-binding assays |
Table 2: Ethanol’s Effects on KCNJ6 Variants
| Parameter | Wild-Type | rs2835859 Haplotype | Post-Ethanol (50 mM) |
|---|---|---|---|
| GIRK2 mRNA levels | 1.0 ± 0.2 | 0.6 ± 0.1* | 1.1 ± 0.3 |
| Neuronal spike rate | 8 Hz | 12 Hz* | 9 Hz |
| PtdIns(4,5)P₂ EC₅₀ | 10 µM | 25 µM* | 12 µM |
| *P < 0.05 vs. wild-type |
