Disease relevance of KCNJ3

• We therefore performed a mutation analysis of KCNJ6 and the related KCNJ3 gene in 38 patients with juvenile myoclonic epilepsy (JME) [1].
• Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice [2].
• CONCLUSIONS: Our data suggests beta-adrenergic receptors and GIRK channels may play a role in breast cancer [3].
• We wanted to determine if GIRK channels were expressed in lung cancers and if a similar link exists in lung cancer [4].
• GIRK (1,2,3,4) mRNA expression was also seen in A549 adenocarcinoma and NCI-H727 carcinoid cell lines [4].

High impact information on KCNJ3

• We report here that free GTP gamma S-activated G alpha i 1, but not G alpha i 2 or G alpha i 3, potently inhibits G beta 1 gamma 2-induced GIRK activity in excised membrane patches of Xenopus oocytes expressing GIRK1 [5].
• At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons [6].
• Here we found that the coupling efficacy (EC(50)) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits [6].
• Function of all GIRK channels was enhanced by intoxicating concentrations of ethanol, but other, related inwardly rectifying potassium channels were not affected [7].
• One of the main targets for this control at postsynaptic membranes is the G protein-coupled potassium channels (GIRK/Kir3), which generate slow inhibitory postsynaptic potentials following the activation of Pertussis toxin-sensitive G protein-coupled receptors [8].

Chemical compound and disease context of KCNJ3

• Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive G proteins [9].
• Decreased GIRK1 protein expression levels were seen after treatment with 0.12% ethanol in MDA-MB-453 breast cancer cells [10].

Biological context of KCNJ3

• 1. A highly informative simple tandem repeat DNA polymorphism of the form (CA)n was identified and used to localize KCNJ3 within the genetic map of the long arm of chromosome 2 [11].
• One of the two single nucleotide polymorphisms (SNPs) examined in one of the inward rectifying potassium channel genes, KCNJ3, was associated with IGE by genotype (P=0.0097), while its association by allele was of borderline significance (P=0.051) [12].
• Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y(12)-mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced G(q)-mediated platelet shape change and intracellular calcium mobilization [13].
• However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin [13].
• GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate [2].

Anatomical context of KCNJ3

• 4. Here we describe the genomic organization of human Kir3.1 (locus designated KCNJ3; cDNA previously named HGIRK1) and the characterization of its major promoter used in hippocampus [14].
• The mutated GIRK and IRK showed normal trafficking to the cell membrane [15].
• The coupling between D3 receptors and native GIRK channels was examined in an AtT-20 mouse pituitary cell line stably expressing the human D3 receptor [16].
• We feel these may be important regulatory pathways since no expression of mRNA of the GIRK channels (1 & 2) was found in hamster pulmonary neuroendocrine cells, a suggested cell of origin for SCLC, nor was GIRK1 or 2 expression found in human small airway epithelial cells [4].
• Using antibodies directed to either GIRK1 or GIRK4, site-directed mutagenesis, and specific glycosidases, we have investigated the effects of glycosylation in the biosynthesis and heteromerization of these proteins expressed in oocytes [17].

Associations of KCNJ3 with chemical compounds

• The whole-cell current of GIRK channels with a constitutively active gate, GIRK2(V188A), [Yi, B. A., Lin, Y. F., Jan, Y. N. & Jan, L. Y. (2001) Neuron 29, 657-667] was also reduced by the same glutamate mutation [15].
• By generating a series of chimeras, we identified a phenylalanine residue, F137, in the pore region of GIRK1 that critically controls channel activity [18].
• F137 is found only in GIRK1, while the remaining GIRK channels possess a conserved serine residue in the analogous position [18].
• RT-PCR and Western blot analyses revealed that AtT-20 cells natively express Kir3.1 and Kir3.2 channel isoforms, but not D2 or D3 dopamine receptors [16].
• The GIRK currents induced by ethanol were also attenuated in the presence of desipramine [2].

Physical interactions of KCNJ3

• Genomic organization and promoter analysis of the human G-protein-coupled K+ channel Kir3.1 (KCNJ3/HGIRK1) [14].
• Moreover, mutations at these GIRK4 sites reduced significantly binding of the channel domains to G beta gamma . The corresponding residues in GIRK1 also showed a critical involvement in G beta gamma sensitivity [19].

Regulatory relationships of KCNJ3

• Cardiac G protein-activated Kir (GIRK) channels may assemble as heterotetrameric polypeptides from two subunits, Kir3.1 and Kir3 [20].
• By contrast, beta5-containing dimers inhibited GIRK channel currents [21].

Other interactions of KCNJ3

• The mutated GIRK1 and GIRK2 retained ion selectivity to K(+) ions [15].
• G protein-gated inwardly rectifying K+ (GIRK) channels, which are important regulators of membrane excitability both in heart and brain, appear to function as heteromultimers [18].
• This finding may partly account for the reason that GIRK4 is not glycosylated at Asn(132), either as a homomer or when coexpressed with GIRK1 [17].
• Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function [17].
• Semiquantitative PCR showed similar transcriptional levels of Kir3.1 and Kir3.2 relative to beta-actin expression in the various GI preparations [22].

Analytical, diagnostic and therapeutic context of KCNJ3

• METHODS: Breast cancer cell lines were screened for GIRK channels by RT-PCR [3].
• The two-microelectrode voltage clamp technique was used to measure the opioid receptor-activated GIRK1/GIRK2 channel responses [23].
• Qualitative PCR demonstrated the presence of Kir3.1 and Kir3.2 transcripts in all smooth muscle cell preparations examined [22].
• Immunohistochemistry using Kir3.1- and Kir3.2-specific antibodies demonstrated channel expression in circular and longitudinal smooth muscle cells [22].
• Molecular cloning of the GIRK channel genes has led to remarkable progress in our understanding of the molecular structure, distribution and functional modulation of these channels [24].

References