HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/C1837    most recent 00405.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Remillard, C. V. Articles by Yuan, J. X.-J. Search for Related Content PubMed PubMed Citation Articles by Remillard, C. V. Articles by Yuan, J. X.-J.

VASCULAR BIOLOGY

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

Departments of Medicine and Psychiatry, Center for Molecular Genetics, School of Medicine, University of California–San Diego, La Jolla, California

Submitted 26 July 2006 ; accepted in final form 24 January 2007

The pore-forming -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.

voltage-gated K⁺ channel; single-nucleotide polymorphism; drug response; etiology

This article has been cited by other articles:

				D. P. McEwen, Q. Li, S. Jackson, P. M. Jenkins, and J. R. Martens Caveolin Regulates Kv1.5 Trafficking to Cholesterol-Rich Membrane Microdomains Mol. Pharmacol., March 1, 2008; 73(3): 678 - 685. [Abstract] [Full Text] [PDF]

				L. Moreno, G. Frazziano, A. Cogolludo, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Role of Protein Kinase C{zeta} and Its Adaptor Protein p62 in Voltage-Gated Potassium Channel Modulation in Pulmonary Arteries Mol. Pharmacol., November 1, 2007; 72(5): 1301 - 1309. [Abstract] [Full Text] [PDF]

				S. J. Fountain, A. Cheong, J. Li, N. Y. Dondas, F. Zeng, I. C. Wood, and D. J. Beech Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2719 - H2725. [Abstract] [Full Text] [PDF]