Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension

Abstract

The pore-forming alpha-subunit, Kv1.5, forms functional voltage-gated K(+) (Kv) channels in human pulmonary artery smooth muscle cells (PASMC) and plays an important role in regulating membrane potential, vascular tone, and PASMC proliferation and apoptosis. Inhibited Kv channel expression and function have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). Here, we report that overexpression of the Kv1.5 channel gene (KCNA5) in human PASMC and other cell lines produced a 15-pS single channel current and a large whole cell current that was sensitive to 4-aminopyridine. Extracellular application of nicotine, bepridil, correolide, and endothelin-1 (ET-1) all significantly and reversibly reduced the Kv1.5 currents, while nicotine and bepridil also accelerated the inactivation kinetics of the currents. Furthermore, we sequenced KCNA5 from IPAH patients and identified 17 single-nucleotide polymorphisms (SNPs); 7 are novel SNPs. There are 12 SNPs in the upstream 5' region, 2 of which may alter transcription factor binding sites in the promoter, 2 nonsynonymous SNPs in the coding region, 2 SNPs in the 3'-untranslated region, and 1 SNP in the 3'-flanking region. Two SNPs may correlate with the nitric oxide-mediated decrease in pulmonary arterial pressure. Allele frequency of two other SNPs in patients with a history of fenfluramine and phentermine use was significantly different from patients who have never taken the anorexigens. These results suggest that 1) Kv1.5 channels are modulated by various agonists (e.g., nicotine and ET-1); 2) novel SNPs in KCNA5 are present in IPAH patients; and 3) SNPs in the promoter and translated regions of KCNA5 may underlie the altered expression and/or function of Kv1.5 channels in PASMC from IPAH patients.

Potassium channels in pulmonary arterial hypertension

“…The possible impacts of single nucleotide polymorphisms in KCNA5 on channel expression and function in PAH have been investigated [63,64]. In taking advantage of large cohorts restricted to the European Caucasian population, a KCNA5 rs10744676 variant, located in the putative promoter of KCNA5, was found to be associated with systemic sclerosis (SSc).…”

Caveolin Regulates Kv1.5 Trafficking to Cholesterol-Rich Membrane Microdomains

“…Kv1.5 is a prominent cardiovascular K ϩ channel that is vital for atrial repolarization in the human heart and the regulation of vascular tone in multiple peripheral vascular beds. Genetic variations of Kv1.5 have been identified in patients with idiopathic pulmonary arterial hypertension (Remillard et al, 2007), whereas mutations cause human atrial fibrillation (Olson et al, 2006). Alterations in the cell surface expression of functional Kv1.5 contribute to the pathophysiology of paroxysmal and persistent atrial fibrillation (Van Wagoner et al, 1997;Tanabe et al, 2006) as well as chronic hypoxic pulmonary hypertension (Michelakis and Weir, 2001;Moudgil et al, 2006).…”

Interplay Between Serotonin Transporter Signaling and Voltage-Gated Potassium Channel (Kv) 1.5 Expression

“…Low levels of Kv1.5 gene expression and channel activity are hallmarks of human and experimental PH, including the chronic-hypoxia and monocrotaline models (Yuan et al, 1998a;Yuan et al, 1998b;Reeve et al, 2001;McMurtry et al, 2004;McMurtry et al, 2005;Bonnet et al, 2006;Guignabert et al, 2006;Young et al, 2006;Remillard et al, 2007;Archer et al, 2008;Guignabert et al, 2009). However, the underlying mechanism of Kv1.5 in PH (Yu et al, 2001), a signal-transducing transcription factor of the AP-1 family, and nuclear factor of activated T cells (NFAT) (Remillard et al, 2007).…”

“…However, the underlying mechanism of Kv1.5 in PH (Yu et al, 2001), a signal-transducing transcription factor of the AP-1 family, and nuclear factor of activated T cells (NFAT) (Remillard et al, 2007). Restoring Kv1.5 gene expression to normal levels in rats reduces PH induced by chronic hypoxia and restores hypoxic pulmonary vasoconstriction (Pozeg et al, 2003).…”