Two-pore channels and inward rectifier potassium current (IK1) determine the resting membrane potential and contributes to the final repolarization in cardiac muscle but its molecular background is still uncertain. Although they are structurally very different, it is thought that both Kir2.x are pore-forming alfa-subunit genes and TWIK1 such as TASK1 two-pore forming alfa-subunit genes may underline the structural base of IK1. Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation that is associated with systolic dysfunction and low resting membrane potential with prolonged action potential duration. Here we examined the contribution of Kir2.x, TWIK1 and TASK1 to IK1 and its possible contribution to electrophysiological remodeling during dilated cardiomyopathy in human ventricular muscle by applying the real-time qPCR, immunofluorescence and Western blot methods. In cardiac left ventricular tissue samples obtained from 17 hearts of patients with dilated cardiomyopathy and from 17 undiseased donors we observed that Kir2.1 and Kir2.3 mRNA and the corresponding protein densities were upregulated while the TWIK1, TASK1 and Kir2.2 mRNA and protein densities with different distribution were down-regulated in dilated cardiomyopathy compared to undiseased control hearts. In addition, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97), a Kir2.x anchoring molecule which exhibits 2.0-2.5 fold reduction was robustly down-regulated in young DCM patients. The results of the present study suggest that both Kir2.x and two-pore channels contribute to IK1 and they can be differently altered in diseased states Such as dilated cardiomyopathy. Such an opportunity may have important new aspect for the explanation of the generally observed physiological alterations and possible therapeutical implications in the future.
This work was supported by grants OTKA NI-6190, DFG, EU FP6 LSHM-CT-2005-018833, EUGeneHeart and TAMOP-4.2.2.-08/1-2008-0013.