Single-nucleotide polymorphisms in vascular Ca2+-activated K+-channel genes and cardiovascular disease

Ion Channels, Receptors and Transporters

Abstract

In the cardiovascular system, Ca2+-activated K+-channels (KCa) are considered crucial mediators in the control of vascular tone and blood pressure by modulating the membrane potential and shaping Ca2+-dependent contraction. Vascular smooth muscle cells express the BKCa channel which fine-tunes contractility by providing a negative feedback on Ca2+-elevations. BKCa channel's ion-conducting α-subunit is encoded by the KCa1.1 gene, and the accessory and Ca2+-sensitivity modulating β1-subunit is encoded by the KCNMB1 gene. Vascular endothelial cells express the calmodulin-gated KCa channels IKCa (encoded by the KCa3.1 gene) and SKCa (encoded by the KCa2.3 gene). These two channels mediate endothelial hyperpolarization and initiate the endothelium-derived hyperpolarizing factor-dilator response. Considering these essential roles of KCa in arterial function, mutations in KCa genes have been suspected to contribute to cardiovascular disease in humans. So far, DNA sequence analysis in the population and patient cohorts has identified single-nucleotide polymorphisms (SNPs) in the BKCa β1-subunit gene as well as in the α-subunit gene (KCa1.1). Some of these SNPs produce amino acid exchanges and evoke alterations of channel functions (“gain-of-function” as well as “loss-of-function”). Moreover, the epidemiological studies showed that the presence of the E65K polymorphism in, e.g., BKCa β1-subunit gene (producing a “gain-of-function”) lowers the prevalence for severe hypertension and myocardial infarction. Other SNPs in the BKCa α-subunit gene and also in the KCa3.1 gene expressed in the endothelium have been suggested to increase the risk of cardiovascular disease. These findings from sequence analysis of human KCa genes, and epidemiological studies thus provide evidence that genetic variations and mutations in KCa channel genes contribute to human cardiovascular disease.

Keywords

Single-nucleotide polymorphism Cardiovascular disease Vascular Ca2+-activated K+-channel gene KCa gene 

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© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Physiology and Pharmacology, Institute of Medical Biology, Faculty of Health ScienceUniversity of Southern DenmarkOdenseDenmark

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