Regional and tissue specific transcript signatures of ion channel genes in the non‐diseased human heart

Abstract

The various cardiac regions have specific action potential properties appropriate to their electrical specialization, resulting from a specific pattern of ion-channel functional expression. The present study addressed regionally defined differential ion-channel expression in the non-diseased human heart with a genomic approach. High-throughput real-time RT-PCR was used to quantify the expression patterns of 79 ion-channel subunit transcripts and related genes in atria, ventricular epicardium and endocardium, and Purkinje fibres isolated from 15 non-diseased human donor hearts. Two-way non-directed hierarchical clustering separated atria, Purkinje fibre and ventricular compartments, but did not show specific patterns for epicardium versus endocardium, nor left-versus right-sided chambers. Genes that characterized the atria (versus ventricles) included Cx40, Kv1.5 and Kir3.1 as expected, but also Cav1.3, Cav3.1, Cavα2δ2, Navβ1, TWIK1, TASK1 and HCN4. Only Kir2.1, RyR2, phospholamban and Kv1.4 showed higher expression in the ventricles. The Purkinje fibre expression-portrait (versus ventricle) included stronger expression of Cx40, Kv4.3, Kir3.1, TWIK1, HCN4, ClC6 and CALM1, along with weaker expression of mRNA encoding Cx43, Kir2.1, KChIP2, the pumps/exchangers Na + ,K + -ATPase, NCX1, SERCA2, and the Ca 2+ -handling proteins RYR2 and CASQ2. Transcripts that were more strongly expressed in epicardium (versus endocardium) included Cav1.2, KChIP2, SERCA2, CALM3 and calcineurin-α. Nav1.5 and Navβ1 were more strongly expressed in the endocardium. For selected genes, RT-PCR data were confirmed at the protein level. This is the first report of the global portrait of regional ion-channel subunit-gene expression in the non-diseased human heart. Our data point to significant regionally determined ion-channel expression differences, with potentially important implications for understanding regional electrophysiology, arrhythmia mechanisms, and responses to ion-channel blocking drugs. Concordance with previous functional studies suggests that regional regulation of cardiac ion-current expression may be primarily transcriptional.

Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo

“…This is in concordance with a previous study where the expression of ion channels was compared between RA and right ventricle (7). Moreover, a loss-of-function mutation of the atrial gene KCNA5 has been linked to atrial fibrillation (22).…”

Effect of NIP-142 on Potassium Channel .ALPHA.-Subunits Kv1.5, Kv4.2 and Kv4.3, and Mouse Atrial Repolarization

“…Alternatively, the difference in potency may be due to the difference in expression systems; human Kv1.5 in our previous study was expressed in HEK293 cells, which is generally known to result in higher sensitivity of expressed ion channel to inhibitory agents compared with the Xenopus oocyte system. The mRNAs for Kv1.5, Kv4.2 and Kv4.3, which underlie the transient outward current, is detected both in human 11) and mouse atria.…”

Biological Pacemaker – Main Ideas and Optimization

“…In ventricular myocytes Kir2.1 is the predominant isoform, although Kir2.2 may also contribute to I K1 to some extent (Dhamoon & Jalife, 2005). Kir2.1 transcripts have been reported to be at the lower levels in the SA node and atria, but much higher in the ventricles (Gaborit et al, 2007). During cardiac development, Kir2.1 is also found at the lowest levels in the mice SA node (Schweizer et al, 2009).…”