Abstract
The human Na+/H+ exchanger isoform 1 (NHE1) is a plasma membrane transport protein that plays an important role in pH regulation in mammalian cells. Because of the generation of protons by intermediary metabolism as well as the negative membrane potential, protons accumulate within the cytosol. Extracellular signal-regulated kinase (ERK)-mediated regulation of NHE1 is important in several human pathologies including in the myocardium in heart disease, as well as in breast cancer as a trigger for growth and metastasis. NHE1 has a N-terminal, a 500 amino acid membrane domain, and a C-terminal 315 amino acid cytosolic domain. The C-terminal domain regulates the membrane domain and its effects on transport are modified by protein binding and phosphorylation. Here, we discuss the physiological regulation of NHE1 by ERK, with an emphasis on the critical effects on structure and function. ERK binds directly to the cytosolic domain at specific binding domains. ERK also phosphorylates NHE1 directly at multiple sites, which enhance NHE1 activity with subsequent downstream physiological effects. The NHE1 cytosolic regulatory tail possesses both ordered and disordered regions, and the disordered regions are stabilized by ERK-mediated phosphorylation at a phosphorylation motif. Overall, ERK pathway mediated phosphorylation modulates the NHE1 tail, and affects the activity, structure, and function of this membrane protein.
Highlights
The mammalian Na+ /H+ exchanger (NHE) is a ubiquitously expressed membrane protein that maintains intracellular pH, removing one intracellular H+ ion in exchange for a single extracellular Na+ ion [1]
The Na+/H+ exchanger isoform 1 (NHE1) cytosolic regulatory tail possesses both ordered and disordered regions, and the disordered regions are stabilized by Extracellular signal-regulated kinase (ERK)-mediated phosphorylation at a phosphorylation motif
NHE1 in the heart is implicated in both myocardial damage from ischemia/reperfusion injury and in promoting hypertrophy
Summary
The mammalian Na+ /H+ exchanger (NHE) is a ubiquitously expressed membrane protein that maintains intracellular pH (pHi ), removing one intracellular H+ ion in exchange for a single extracellular Na+ ion [1]. NHE1 (isoform one) in the heart is implicated in both myocardial damage from ischemia/reperfusion injury and in promoting hypertrophy (reviewed in the works of [2,3]) This membrane protein consists of two domains. Transmembrane Na+ /H+ exchange is ubiquitous across all phyla and kingdoms, so NHEs play an important role in many species. The CPA2 family can catalyze electrogenic or electroneutral activity This includes Na+ , K+ /H+ exchangers and the electrogenic E. coli NhaA antiporter. The region between TM9 and TM10 (extracellular loop 5, approximately amino acids 362–411) was shown to be extracellular based on cysteine scanning and accessibility experiments Part of this segment was suggested to be associated with the lipid bilayer based on its hydrophobicity and a lack of accessibility of a few residues in cysteine accessibility studies. That the structure of the cytosolic tail domain shows conservation (discussed below) [34]
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