Mechanism of Inhibition of Na+-H+ Exchanger (NHE1) by ATP Depletion: Implications for Myocardial Ischemia
Na+-H+ exchange activity is metabolic energy dependent and may be inhibited when cell ATP level is reduced during myocardial ischemia. We found that ATP depletion inhibits activity of the cardiac isofom of the Na+-H+ exchanger (NHE1) by decreasing its apparent affinity for cytoplasmic H+, but not its Vmax value. By using a set of deletion mutants of the regulatory cytoplasmic domain of NHE1, we identified a 26-amino-acid-containing segment required to confer sensitivity to ATP depletion. This segment is localized within the most amino-terminal subdomain of the cytoplasmic domain that is critically important for the maintenance of high pHi sensitivity of NHE1 under nomal physiological condltions, as well as for upregulation of pHi sensitivity induced by stimulation with growth factors.
KeywordsCytoplasmic Domain Modifier Site Intracellular Acidosis Flexible Loop Domain Internal Deletion Mutant
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