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Sustained acidosis and phenylephrine activate the myocardial Na+/H+ exchanger through phosphorylation of Ser770 and Ser771 Open Access


Other title
sustained acidosis
p90 risobomal S6 kinase
extracellular regulated kinase 1/2
sodium hydrogen exchanger
Type of item
Degree grantor
University of Alberta
Author or creator
Coccaro, Ersilia
Supervisor and department
Fliegel, Larry (Biochemistry)
Examining committee member and department
Young, Howard (Biochemistry)
Brindley, David (Biochemistry)
Schulz, Richard (Pharmacology)
Walsh, Michael (Biochemistry and Molecular Biology)
Holmes, Charles (Biochemistry)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein that regulates myocardial intracellular pH. Inhibition of NHE1 prevents hypertrophy and reduces ischemia-reperfusion (I/R) injury in animal models. To understand the regulation of NHE1 in the myocardium by phosphorylation we constructed adenoviruses, which express wild type or mutant cDNA for NHE1. Additionally, wild type and mutant NHE1 had mutations Leu163Phe/Gly174Ser, which increases NHE1 resistance to EMD87580 (NHE1 inhibitor) by 100-fold. This allowed measurement of exogenous NHE1 activity while inhibiting endogenous NHE1 activity. We examined the effects of a series of mutations of phosphorylation sites in the cytosolic domain of NHE1. Sustained intracellular acidosis and phenylephrine caused an ERK-dependent activation of NHE1 activity and phosphorylation levels. We demonstrated that amino acids Ser770 and Ser771 were essential for activation of NHE1 activity in isolated rat cardiomyocytes by sustained intracellular acidosis and phenylephrine. Furthermore, mutation of Ser770 and Ser771 to Ala prevented increased NHE1 phosphorylation by sustained intracellular acidosis and phenylephrine. This was found to occur in an ERK-dependent manner. Taken together, our results demonstrate that both sustained intracellular acidosis and phenylephrine rapidly activate the NHE1 protein in isolated cardiac cells via an ERK-dependent pathway that acts on the common amino acids Ser770 and Ser771 of the C-terminal tail of NHE1.
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