Disease relevance of KCNA5

• A long-range restriction map of an 800-kb region was constructed and used to refine the mesothelioma breakpoint to a region of approximately 100 kb, flanked by the potassium channel genes KCNA1 and KCNA5 [1].
• We have shown that acute hypoxia selectively inhibits I(K(V)) through KCNA5 channels in PASMC [2].
• Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial hypertension (IPAH) [3].
• Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation [4].
• Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients [5].

High impact information on KCNA5

• A delayed rectifier K+ channel such as hPCN1 could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion [6].
• Two-microelectrode voltage-clamp recordings of oocytes injected with hPCN1 RNA revealed a voltage-dependent outward K+ current that inactivated slowly with time [6].
• From 70 CEPH parents screened with a StyI RFLP for hPCN1, four informative families were found each with both parental and maternal grandparents and 6-11 children per family [7].
• Dinucleotide repeat polymorphism at the KCNA5 locus [8].
• In the present study, we have analyzed this region in the human renal proximal tubular epithelial cell line HK-2 [9].

Biological context of KCNA5

• Molecular biological characterization of the YAC-insert DNAs revealed that three KCNA genes--KCNA1, KCNA5, KCNA6--are clustered within approximately 300 kb of insert-DNA derived from chromosome 12p13 [10].
• Overexpression of human KCNA5 increases IK V and enhances apoptosis [3].
• KCNA5 is a Kv channel alpha-subunit that forms functional Kv channels in PASMC and regulates resting membrane potential [2].
• Transient transfection of KCNA5 caused 25- to 34-fold increase in KCNA5 channel protein level and 24- to 29-fold increase in Kv channel current (I(K(V))) at +60 mV in COS-7 and rat PASMC, respectively [3].
• In two patients with arrhythmia and cardiac arrest, we identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia [5].

Anatomical context of KCNA5

• Reduction of Po(2) from 145 to 35 mmHg reduced I(K(V)) by approximately 40% in rat PASMC transfected with human KCNA5 but had no effect on I(K(V)) in KCNA5-transfected rat MASMC (or HEK and COS cells) [2].
• Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells [2].
• Immunoblotting analysis of human liver microsome preparations revealed that human cytochrome P-450 PCN1 (hPCN1, Mr approximately 52,000) was expressed in each of 40 individual specimens examined [11].
• The interaction of quinidine with a cloned human cardiac potassium channel (HK2) expressed in a stable mouse L cell line was studied using the whole-cell tight-seal voltage-clamp technique [12].
• NF25 and hPCN1 were functionally expressed in yeast microsomes, yielding proteins with an absorption maximum at 448 nm in the CO-reduced difference spectrum [13].

Associations of KCNA5 with chemical compounds

• Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K+ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells [3].
• Both enzymes also catalyzed 6 beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione, although hPCN1 exhibited several-fold higher expressed activity than hPCN3 [11].
• Clear differences were also detected in their catalytic activities toward the immunosuppressive drug cyclosporine, with two hydroxylated metabolites (M1 and M17) and one demethylated metabolite (M21) formed by hPCN1 but only one metabolite (M1) formed by hPCN3 [11].
• These data indicate that 1) the charged form of quinidine blocks the HK2 channel after it opens, 2) binding occurs within the transmembrane electrical field (probably in or near the ion permeation pathway), and 3) unbinding is required before the channel can close [12].
• The effect of clofilium on potassium conductance was studied in excised membrane patches from Chinese hamster ovary cells stably transfected with the Kv1.5/hPCN1 delayed rectifier K+ channel gene [14].

Regulatory relationships of KCNA5

• These studies establish that hPCN3 is a newly described cytochrome P-450 that is differentially expressed in the adult human population and that has overlapping substrate specificity compared to hPCN1 for metabolism of steroid and drug substrates [11].

Other interactions of KCNA5

• Gene expression studies of Shaker KV1 transcripts have shown that of the dominant species present in arterial SMCs, KV1.2 expression is higher, whereas KV1.5 is the same in SMCs from hypertensive compared to normal animals [15].
• The library was screened with an hPCN1 cDNA probe resulting in the isolation of a unique full-length cDNA that was sequenced and shown to encode hPCN3 [11].
• Three natural allelic cDNAs coding for P-450 3A4, the major form in human liver, namely NF25, NF10 and hPCN1, have been expressed in Saccharomyces cerevisiae [13].
• We found that the mRNA levels of KV1.5, HERG and KVLQT1 were all significantly decreased in patients with persistent atrial fibrillation for more than 3 months [16].

Analytical, diagnostic and therapeutic context of KCNA5

• The electrophysiological characteristics of hPCN1 were determined after microinjection of synthetic RNA into Xenopus oocytes [6].

References