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The biophysical and molecular basis of intracellular pH sensing by Na + /H + exchanger‐3
Author(s) -
Babich Victor,
Vadnagara Komal,
Di Sole Francesca
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-225466
Subject(s) - chemistry , intracellular ph , intracellular , anion exchanger , biophysics , physics , radiochemistry , ion exchange , biochemistry , ion , biology , organic chemistry
Epithelial Na + /H + exchanger‐3 (NHE3) transport is fundamental for renal and intestinal sodium reabsorption. Cytoplasmic protons are thought to serve as allosteric modifiers of the exchanger and to trigger its transport through protein conformational change. This effect presupposes an intracellular pH (pH i ) dependence of NHE3 activity, although the biophysical and molecular basis of NHE3 pH i sensitivity have not been defined. NHE3, when complexed with the calcineurin homologous protein‐1 (CHP1), had a shift in pH i sensitivity (0.4 units) toward the acidic side in comparison with NHE3 alone, as measured by oscillating pH electrodes combined with whole‐cell patch clamping. Indeed, CHP1 interaction with NHE3 inhibited NHE3 transport in a pH i ‐dependent manner. CHP1 binding to NHE3 also affected its acute regulation. Intracellular perfusion of peptide from the CHP1 binding region (or pH i modification to reduce the CHP1 amount bound to NHE3) was permissive and cooperative for dopamine inhibition of NHE3 but reversed that of adenosine. Thus, CHP1 interaction with NHE3 apparently establishes the exchanger set point for pH i , and modification in this set point is effective in the hormonal stimuli‐mediated regulation of NHE3. CHP1 may serve as a regulatory cofactor for NHE3 conformational change, dependent on intracellular protonation.—Babich V., Vadnagara K., Di Sole, F. The biophysical and molecular basis of intracellular pH sensing by the Na + /H + exchanger‐3. FASEB J . 27, 4646–4658 (2013). www.fasebj.org