Aims: 

Cardiac contractility is under the control of intracellular [Ca] which is linked to intracellular [Na] through the Na/Ca-exchanger (NCX). Intracellular [Na] is in turn regulated by the Na/K-ATPase (NKA). Recent research suggest that important crosstalk between Ca and Na handling membrane proteins occurs through defined microdomains. We aim to investigate how these microdomains are altered during cardiac disease.

Methods: 

Ca and Na handling were studied in cardiomyocytes using fluorescence and microelectrode techniques.

Results: 

The NKA 2-isoform was observed to be efficiently coupled to NCX by colocalisation in discrete locations in the t-tubules of rat cardiomyocytes. This coupling involves a shared subsarcolemmal microdomain of Na and constitutes an important regulatory mechanism of cardiomyocyte contractility. In a rat model of heart failure, altered t-tubule network structure and downregulation of the NKA 2-isoform caused attenuated control of NCX. It has been reported that NKA and NCX are anchored to an intracellular polypeptide called ankyrin-B. Disruption of the NKA-ankyrin-B binding using disruptor peptides caused a reduction in NKA current. A similar reduction was observed in heterozygous ankyrin-B KO mice, indicating that ankyrin-B is important for NKA regulation. These mice also exhibited increased propensity for Ca waves, which likely results from increased SR Ca load. However, the increased SR Ca load was not due to altered microdomain crosstalk between NCX and NKA, but may instead result from a direct regulatory effect of ankyrin-B on NKA, or through altered global intracellular [Na] and NCX.

Conclusion: 

Tight regulation of the crosstalk between NKA and NCX plays an important role in inter-regulation of Na and Ca in cardiac disease.