Disease relevance of KCNJ5

• Defects in insulin secretion are a common feature of non-insulin-dependent diabetes mellitus (NIDDM), and the beta-cell KATP that couples metabolism and membrane potential is a candidate for contributing to the development of this clinically and genetically heterogeneous disorder [1].
• GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435 [2].
• Indeed, recent studies from our laboratory and others have suggested that activation of KATP channels during anoxia is important in the response and adaptation of central neurons to hypoxia [3].
• Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism [4].
• Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy [5].

Psychiatry related information on KCNJ5

• A KATP-channel opener as a potential treatment modality for erectile dysfunction [6].

High impact information on KCNJ5

• Two KIR6.x genes and two SUR genes have been identified, and combinations of subunits give rise to KATP channel subtypes found in pancreatic beta-cells, neurons, and cardiac, skeletal, and smooth muscle [7].
• Adenosine 5'-triphosphate-sensitive potassium (KATP) channels couple metabolic events to membrane electrical activity in a variety of cell types [7].
• In anoxic cardiac ventricular muscle KATP channels are believed to be responsible for shortening the action potential, and it has been proposed that a fall in ATP concentration during metabolic exhaustion increases the activity of KATP channels in skeletal muscle, which may reduce excitability [8].
• This concentration is much higher than the intracellular ATP concentration required to half block the KATP-channel current in either cardiac muscle (0.1 mM) or skeletal muscle (0.14 mM), indicating that the open-state probability of KATP channels is normally very low in intact muscle [8].
• Decreases in the ADP level as glucose is metabolized result in KATP channel closure [9].

Chemical compound and disease context of KCNJ5

• The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity [9].
• During steady-state vasoconstriction induced in isolated ferret lungs by moderate hypoxia, cromakalim caused dose-dependent vasodilation (EC50 = 7 x 10(-7) M) which was reversed by glibenclamide (IC50 = 8 x 10(-7) M), indicating that KATP channels were present and capable of modulating vascular tone [10].
• These findings suggest that in the ferret lung (a) severe hypoxia decreased ATP concentration and thereby opened KATP channels, resulting in increased K+ efflux, hyperpolarization, vasodilation, and reversal of the initial vasoconstrictor response; and (b) hyperglycemia prevented this sequence of events [10].
• CONCLUSIONS: In humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATP channels [11].
• KATP channels also are found in the heart where they are involved in the response to cardiac ischemia: they also are blocked by phentolamine [12].

Biological context of KCNJ5

• Assignment of KATP-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24 [13].
• Isolation of a cDNA clone encoding a KATP channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1, and linkage studies with NIDDM [1].
• GIRK1 membrane-spanning domain 1 was required for optimal glycosylation at Asn(119) because a chimera that contained GIRK4 membrane-spanning domain 1 significantly reduced the addition of a carbohydrate structure at this site [14].
• We have analyzed a series of mutant and chimeric channels suggesting that the GIRK4 subunit is capable of responding to G(q) signals and that the resulting current inhibition does not occur via phosphorylation of a canonical PKC site on the channel itself [15].
• Single-channel recordings of the active chimeras exhibited patterns of activities with open-time kinetics and conductance characteristics representative of those of GIRK4, indicating that the presence of the GIRK1 C-terminal region caused an increase in the frequency of channel openings without affecting their duration [16].

Anatomical context of KCNJ5

• When expressed in Xenopus oocytes, GIRK4 yielded functional GIRK channels with activity that was enhanced by the stimulation of coexpressed serotonin 1A receptors [17].
• RNA blotting showed that KATP mRNA was present in insulin-secreting cells and brain but not in heart [1].
• Additional motifs in Kir3.2 and Kir3.4 control the trafficking between endosome and plasma membrane [18].
• We report here that treatment of chick embryos in ovo with muscarinic agonist causes decreases in mRNA levels encoding GIRK1 and GIRK4 in atria but does not alter GIRK1 expression in ventricles [19].
• In order to identify KATP channels from human brain, we performed a polymerase chain reaction (PCR) using human cerebral cortex mRNA and primers derived from the ROMK1 sequence, a cDNA clone encoding an ATP-regulated potassium channel, recently isolated from rat kidney [3].

Associations of KCNJ5 with chemical compounds

• The metabolism of glucose in insulin-secreting cells leads to closure of ATP-sensitive K+ channels (KATP), an event that initiates the insulin secretory process [1].
• We show that mutation of charged glutamate and arginine residues behind the selectivity filter in the Kir3.1/Kir3.4 K+ channel reduces or abolishes K+ selectivity, comparable with previously reported effects in the Kir2.1 K+ channel [20].
• Complementary mutation of the equivalent amino acid in Kir3.4 to produce Kir3.4(S143T)(D223N) significantly reduced the sensitivity of the channel to arachidonic acid- and Et-1-induced inhibition [21].
• RESULTS: mRNA levels of transient outward channel (Kv4.3), acetylcholine-dependent potassium channel (Kir3.4) and ATP-dependent potassium channel (Kir6.2) were reduced in patients with persistent AF (-35%, -47% and -36%, respectively, p < 0.05), whereas only Kv4.3 mRNA level was reduced in patients with paroxysmal AF (-29%, p = 0.03) [22].
• Effects of ACh and adenosine mediated by Kir3.1 and Kir3.4 on ferret ventricular cells [23].

Physical interactions of KCNJ5

• 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 [24].

Other interactions of KCNJ5

• The single-point mutant GIRK4(S143F) behaved as a GIRK1 analog, forming multimers with GIRK2, GIRK4, or GIRK5 channels that exhibited prolonged single-channel open-time duration and enhanced activity compared with that of homomultimers [25].
• 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 [14].
• Transcripts for Kir3.3 and Kir3.4 were not detected in the same preparations [26].
• Considerable genetic, molecular, physiological and pharmacological evidence now exists to support a role for K(+) channels such as KCNQ2/Q3, Kv1.1, KATP and GIRK2 in the control of neuronal excitability and epileptogenesis [27].
• In a multivariable analysis, high ERG expression (P < .001) and the presence of MLL PTD (P = .027) predicted worse CIR [28].

Analytical, diagnostic and therapeutic context of KCNJ5

• 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 [14].
• Cs+ caused voltage-dependent block of GIRK1/GIRK4 current (measured with the two-microelectrode voltage-clamp technique) [29].
• Ischemic preconditioning: from adenosine receptor to KATP channel [30].
• In some animal species, myocardial preconditioning appears to be due to activation of ATP-sensitive K+ (KATP) channels [11].
• The aim of this study was to establish whether glibenclamide, a selective KATP channel blocker, abolishes the ischemic preconditioning observed in humans during coronary angioplasty following repeated balloon inflations [11].

References