KCNJ9 Membrane Protein Introduction

Introduction of KCNJ9

KCNJ9 (also well known as K_ir3.3 and GIRK-3) is a member of the G-protein-activated inwardly rectifying potassium (GIRK) channel family, which is encoded by the KCNJ9 gene. As one of four identified K_ir3 channels, KCNJ9 can form heterotetramers together with K_ir3.1 (KCNJ3), K_ir3.2 (KCNJ6) or K_ir3.4 (KCNJ5) in neurons, meanwhile the assemblies of K_ir3 subunits is various among different tissues and cell types in every channel, corresponding to their diverse functional roles. Like other members of the K_ir family, KCNJ9 also contains two transmembrane helixes (M1 and M2), a pore loop between M1 and M2, and cytoplasmic N- and C-terminal domains. Gene KCNJ9 has been localized to chromosome 1q21-q23. Following activation of G_i/o-coupled receptors, KCNJ9 can mediate slow inhibitory postsynaptic potentials, subsequently regulates membrane excitability in neuronal, cardiac, and endocrine cells. KCNJ9 may present different transcripts with various single nucleotide polymorphisms (SNPs) in various human tissues.

Function of KCNJ9 Membrane Protein

Because of suggestive linkage to Type II diabetes mellitus in the Pima Indian population, the KCNJ9 locus is a good functional candidate gene, with the ability to regulate membrane potential resembles the role of K_ATP channels in glucose-induced insulin secretion in pancreatic beta cells. The responses to cocaine self-administration and hyperexcitability during withdrawal from sedative-hypnotic drugs (pentobarbital, zolpidem, ethanol, etc.) are reduced in KCNJ9^-/- transgenic mice, suggesting the important role in the neuronal activity and plasticity evoked by drugs of abuse. It is also documented that KCNJ9 in VTA neurons is essential for the activation of the mesolimbic DA system by ethanol, moreover, it can selectively modulate excessive drinking without influencing the behavioral manifestations of ethanol intoxication. So KCNJ9 has been recognized as a critical determinant of DA neuron sensitivity to drugs of abuse. KCNJ9 also contributes to analgesia from multiple drug classes. A class of large inhibitory neurons, including Purkinje cells and a novel type of interneuron in CA3 region of rodent hippocampus, are characterized by an axonal sorting of KCNJ9 and these distinctive neurons can modulate the activity of CA3 circuitries and consequently memory processing in the hippocampus.

Fig.1 The PARC SNPs of KCNJ9. (Choi, 2011)

Application of KCNJ9 Membrane Protein in Literature

1. Herman M.A., et al. GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Proceedings of the National Academy of Sciences. 2015, 201416146. PubMed ID: 25964320
   
   

   In this article, the authors revealed that genetic ablation of GIRK3 will prevent ethanol from activating the mesolimbic dopaminergic pathway and enhances binge-like drinking, so GIRK3 appears to be a critical gatekeeper of ethanol incentive salience.

2. Grosse G., et al. Axonal sorting of Kir3.3 defines a GABA-containing neuron in the CA3 region of rodent hippocampus. Molecular and Cellular Neuroscience. 2003, 24(3): 709-724. PubMed ID: 14664820
   
   

   This article reported a new type of large GABA-containing neuron in rodent hippocampus possessing an axonal sorting of the potassium channel Kir3.3, which might modulate the activity of CA3 circuitries and consequently memory processing in the hippocampus.

3. Smith S.B., et al. Quantitative trait locus and computational mapping identifies Kcnj9 (GIRK3) as a candidate gene affecting analgesia from multiple drug classes. Pharmacogenetics and genomics. 2008, 18(3): 231-241. PubMed ID: 18300945
   
   

   The authors found that Kcnj9 knockout mice had attenuated analgesic responses, providing strong evidence that Kcnj9 (GIRK3) may be a candidate gene affecting analgesia from multiple drug classes. Computational (in silico) genetic analysis of analgesic responses showed that Kcnj9 was partially responsible for the genetic mediation of pain inhibition.

4. Vaughn J., et al. Genomic structure and expression of human KCNJ9 (Kir3.3/GIRK3). Biochemical and biophysical research communications. 2000, 274(2): 302-309. PubMed ID: 19759313
   
   

   The authors analyzed the genomic structure of the KCNJ9 gene and demonstrated that KCNJ9 contained one noncoding and two coding exons separated by ~2.2 and ~2.6 kb introns, respectively. Moreover, they identified that the KCNJ9 gene was mapped to chromosome 1q21-23 as a candidate gene for Type II diabetes mellitus in the Pima Indian population.

5. Walter N.A.R., et al. High throughput sequencing in mice: a platform comparison identifies a preponderance of cryptic SNPs. BMC genomics. 2009, 10(1): 379. PubMed ID: 19686600
   
   

   The authors used high-throughput sequencing technique to identify a preponderance of cryptic SNPs, and they identified 18 new SNPs within 2 kb upstream of the transcriptional start site as well as nine new SNPs in the 3' untranslated region of KCNJ9.

KCNJ9 Preparation Options

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Reference

1. Choi M, et al. (2011). K⁺ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 331(6018): 768-772.

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