KCNA5

Official Full Name

potassium voltage-gated channel subfamily A member 5

Organism

Homo sapiens

GeneID

3741

Background

Potassium channels represent the most complex class of voltage-gated ino channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Defects in this gene are a cause of familial atrial fibrillation type 7 (ATFB7). [provided by RefSeq, May 2012]

Synonyms

HK2; HCK1; PCN1; ATFB7; HPCN1; KV1.5;

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Detailed Information

Recent Research

KCNA5 gene-encoded Kv1.5 potassium channel is a subtype of Kv1 potassium channel. The channel consists of α and β subunits; four identical αsubunits form a homologous tetramer, forming the pore region and voltage-sensitive area of Kv1.5 channel complex. Each α subunit contains six transmembrane protein molecule areas (S1 to S6), respectively, constituting the subjects of voltage-gated channels, N and C-terminal subunit. β subunit plays a supporting role, maintaining the stability of Kvl.5 channel as a chaperone together with associated membrane protein.

Kv1.5 Channel Function in Physiological and Pathological Conditions

Kv1.5 channel is expressed in many cell types in the human body, including atrial myocytes, pulmonary arterial smooth muscle cells (PASMCs), GH3 pituitary cells, oligodendrocyte precursor cells, macrophages, somato dendritic Purkinje cells of the cerebellum and cancer cells. Besides, the Kv1.5 channel is of particular importance in O₂-sensitive tissues, as it possesses an O₂-sensitive channel and its expression, at both a protein and transcript level, is directly altered by oxidative factors, mainly HIF-1α and hydrogen peroxide (H₂O₂). Therefore, due to its voltage and oxygen-sensitivity the Kv1.5 channel has a dynamic role in physiologic and pathophysiological states that are associated with ROS and oxidative stress. It was recently shown that exposure of neuronal cells to acute hypoxia and glucose deprivation leads to apoptosis and that this ischemia-induced cell death is associated with upregulation of Kv1.5 expression. Several reports show that Kv1.5 expression is reduced in human cancers, and in gliomas, loss of expression is directly correlated with tumor aggression, suggesting that loss of the channel might contribute to tumor progression. Moreover, recent studies demonstrated that restoration of normal mitochondrial function and redox tension by use of the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) resulted in derepression of KCNA5 transcription and induction of Kv1.5-dependent apoptosis.

Kv1.5 and Atrium

In the cardiovascular system, specifically in the human atrium, Kv1.5 underlies the ultra-rapid delayed recitifier current (I_Kur), important for atrial repolarization and action potential duration. Therefore, the Kv1.5 channel is important for returning the membrane potential of atrial myocytes from a depolarized state (~52 mV) back towards its resting membrane potential (~-80 mV). In atrial myocytes, the Kv1.5 channel current is activated at potentials in the range of -20 mV to +50 mV. Kv1.5 plays an important role in atrial fibrillation (AF). AF is the most common cardiac arrhythmia present in the population. Shortening of the atrial effective refractory period of the atrium is an important factor in acute and persistent AF. An early study established that patients in chronic AF have electrophysiological and physiological remodeling and a consequence of this remodeling is the down-regulation of Kv1.5 channel expression. One aspect associated with structural and electrical remodeling of the heart in AF, is the excessive production of ROS .Furthermore, the activation of Kv1.5 reduces action potential duration and leads to the shortening of the atrial refractory period. In particular, it is thought that initial activation of the Kv1.5 channel in acute AF contributes to the continuation of AF, leading to chronic AF and the eventual down-regulation of the Kv1.5 channel.

Kv1.5 and Pulmonary Vasculature

PASMCs rely on Kv channels, in particular the Kv1.5 channel, to determine resting membrane potential and the concentration of cytosolic free Ca²⁺. In the pulmonary vasculature, exposure to acute hypoxia inhibits Kv channels, increases cytosolic Ca²⁺ depolarizes the PASMCs and causes pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction is mediated by the inhibition of Kv potassium channels in PASMCs, predominantly via acute down-regulation of the O₂-sensitive Kv1.5 channel. In PAH, conditions of acute and chronic hypoxia result in the significant down-regulation of Kv1.5 channel expression and the Kv1.5-encoding gene transcript KCNA5. Therefore, loss of Kv1.5 expression in is a contributing factor in the pathogenesis of PAH. Recently, it was discovered that the Kv1.5 channel is part of a key pathway, the mitochondria-ROS-HIF-Kv pathway, whose disruption contributes to the development of polycyclic aromatic hydrocarbon (PAH). It was elucidated that under hypoxic conditions, HIF-1 represses KCNA5 and ROS withdrawal inhibits the opening of Kv1.5 channels. This results in pulmonary vasoconstriction, the eventual hyperpolarization of the mitochondria and ultimately disrupts the mitochondria- ROS-HIF-Kv pathway. Furthermore, re-introducing the Kv1.5 channel improves pulmonary hypertension, as it restores the O₂-sensitive current and reduces pulmonary vascular resistance. And the Kv1.5 channel also underlies mitochondrial-mediated cell death in PAH, due to its involvement in the mitochondria-ROS-HIF-Kv path way and the discovery that the pro-apoptotic activator cytochrome-c activates Kv channels, while the anti-apoptotic bcl-2 inhibits Kv channels.

Kv1.5 and Cell Proliferation and Apoptosis

The Kv1.5 channel has been shown to regulate the G1/S transition in the cell cycle. Several reports showed that DNA methylation and repression of KCNA5 contribute to cell-cycle progression and that reversion of promoter methylation and KCNA5 de-repression is associated with growth inhibition and cell-cycle arrest. Moreover, specific pharmacologic inhibition of the Kv1.5 channel function partially restores proliferation in Ewing sarcoma cells that have been exposed to decitabine. Reactivation of silenced Kv1.5 channels can inhibit cancer proliferation. It was discovered that Kv1.5 inhibited skeletal muscle cell proliferation at the G1/S transition, through a mechanism that increased cyclin-dependent kinase inhibitors p21 and p27 and decreased expression of cyclins A and D1. As Kv1.5 and KCNA5 expression are down-regulated in many human cancers (e.g. glioblastoma and lymphoma). In lymphocytes, down-regulation of Kv1.5 expression prevented apoptosis, while in several cancer cell lines, including M059K (glioblastoma), A549 (non-small-cell lung) and MCF-7 (breast) cancer cells, reactivation of the Kv1.5 channel induced apoptosis. Besides, in the cell line study it was discovered that the transcription factor, NFAT directly represses KCNA5, and release of this repression leads to apoptotic cell death.

References:

Ryland K E. The Epigenetic Regulation of KCNA5 in Pediatric Solid Tumors and its Role in Cancer Biology. 2015.
Ryland K E, et al. Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress. Oncogene, 2015, 34(35):4591-4600.
Ryland K E, et al. Promoter Methylation Analysis Reveals that KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation. Molecular Cancer Research Mcr, 2015, 14(1):26.
Li T, et al. KCNA5 gene polymorphism associate with idiopathic atrial fibrillation. International Journal of Clinical & Experimental Medicine, 2015, 8(6):9890.

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