Protein-protein interactions in the regulation of the cardiac sodium pump by phospholemman

Hormones such as adrenaline act on the individual cells of the heart (?myocytes?) to cause the whole heart to change its behaviour according to the needs of the body. This is an exquisitely regulated process that means the heart?s output matches the body?s requirements. Understanding how exposure to hormones causes the whole heart to change its behaviour is crucial in developing an understanding of what can go wrong in heart disease.
Within a myocyte, hormonal signals are transmitted into the cell by groups of proteins (protein ?complexes?). The way these complexes work depends on the proteins involved. We have evidence that a protein complex forms between two proteins, dok-7 and phospholemman. Phospholemman is responsible for transmitting signals from hormones to another protein, the sodium pump, one of the most important enzymes in the heart. The sodium pump is responsible for moving ions across cell membranes, and indirectly it controls many processes that keep the heart alive and allow it to beat. Understanding the relationship between dok-7, phospholemman and the sodium pump will greatly improve our understanding of the way the heart responds to hormones, and possibly why diseased hearts are less able to do so.

The primary active means of ion transport in the cardiomyocyte sarcolemma is the sodium pump. Acute regulation of the cardiac sodium pump by extracellular stimuli is crucial in allowing the heart to match its output to systemic requirements. Interventions that influence either sodium pump activity, or indirectly the transmembrane sodium gradient, profoundly affect cardiac function. Misregulation of the sodium pump can lead to cardiac insufficiency and heart failure. Phospholemman (PLM) is a novel sodium pump accessory protein that provides the link between kinase activity and modulation of sodium pump function. PLM exerts a tonic inhibition on the sodium pump that is relieved, and activity is in fact stimulated, by phosphorylation of PLM by a variety of kinases. Spatial and temporal control of signalling to PLM is key in controlling sodium pump function. The proteins that direct kinases and phosphatases to the PLM / sodium pump complex are unknown. We have preliminary evidence that the cytoplasmic scaffold protein dok-7, which contains N terminal plekstrin homology and phosphotyrosine binding domains interacts with PLM through its C terminus. Hence dok-7 has the potential to bring PLM together with signalling molecules. This proposal will characterise the functional consequences of this interaction, both in terms of kinase signalling to PLM, and PLM regulation of sodium pump function. Understanding the relationship between dok-7, PLM and the sodium pump will expand our knowledge of basic cardiac physiology and biochemistry, and may identify novel targets for treatment of cardiac ischemia, hypertrophy and heart failure.