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1)  Describe the structure and functions of the Sodium Proton Exchangers.

2)  Identify the underlying mechanism of a calcium myristoyl switch.

3)  Understand how the Calcineurin B homologous protein isoform 3 regulates the function of the Sodium Proton Exchanger Isoform 1

Restoration of cardiac intracellular pH (pHi) following acidification is of crucial importance for the maintenance of myocardial contractility. The predominant mechanism responsible for this is the function of the sodium/hydrogen exchanger isoform 1 (NHE1), which is the primary isoform of mammalian myocardium. NHE1 is localized predominantly at the intercalated disks and along the transverse tubular system where it is believed to play an essential role in cardiac pH homeostasis, impulse conductance and excitation-contraction coupling. However, the factors that control the membrane targeting and regulation of NHE1 in heart are poorly understood. Yeast-two hybrid screening identified a cardiac-predominant member of the calcineurin B homologous protein (CHP) family, called CHP3/Tescalcin, that binds directly to the cytoplasmic C-terminal domain of NHE1. However, the functional significance of this interaction has yet to be elucidated. This study undertook biochemical and cellular analysis to determine both the significance of the NHE1-CHP3 complex for pH regulation in cardiac tissue, as well as the significance of calcium-binding in this complex. These studies suggest that CHP3 acts to stabilize the mature form of NHE1 at the plasma membrane, rather than exhibiting a kinetic effect. DiagramDescription automatically generated

This results in higher expression of the exchanger at the cellular membrane, accounting for this increase in exchange activity. Furthermore, the binding of Calcium to the CHP3 protein is crucial for the stability of this NHE1-CHP3 complex, suggesting the CHP3 acts as the calcium-myristoyl switch protein.

 

Restoration of cardiac intracellular pH (pHi) following acidification is of crucial importance for the maintenance of myocardial contractility. The predominant mechanism responsible for this is the function of the sodium/hydrogen exchanger isoform 1 (NHE1), which is the primary isoform of mammalian myocardium. NHE1 is localized predominantly at the intercalated disks and along the transverse tubular system where it is believed to play an essential role in cardiac pH homeostasis, impulse conductance and excitation-contraction coupling. However, the factors that control the membrane targeting and regulation of NHE1 in heart are poorly understood. Yeast-two hybrid screening identified a cardiac-predominant member of the calcineurin B homologous protein (CHP) family, called CHP3/Tescalcin, that binds directly to the cytoplasmic C-terminal domain of NHE1. However, the functional significance of this interaction has yet to be elucidated. This study undertook biochemical and cellular analysis to determine both the significance of the NHE1-CHP3 complex for pH regulation in cardiac tissue, as well as the significance of calcium-binding in this complex. These studies suggest that CHP3 acts to stabilize the mature form of NHE1 at the plasma membrane, rather than exhibiting a kinetic effect. DiagramDescription automatically generated

This results in higher expression of the exchanger at the cellular membrane, accounting for this increase in exchange activity. Furthermore, the binding of Calcium to the CHP3 protein is crucial for the stability of this NHE1-CHP3 complex, suggesting the CHP3 acts as the calcium-myristoyl switch protein.

 
Zaun HC, Shrier A, Orlowski J. Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform. J Biol Chem. 2008, 283(18): 12456-67.

Zaun HC, Shrier A, Orlowski J. N-myristoylation and Ca2+ binding of calcineurin B homologous protein CHP3 are required to enhance Na+/H+ exchanger NHE1 half-life and activity at the plasma membrane. J Biol Chem. 2012; 287(44): 36883-95.
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