ArticleThe Journal of biological chemistry2011
Proton-sensing Ca2+ binding domains regulate the cardiac Na+/Ca2+ exchanger.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 67 citations in OpenAlex.
- Article
- Ablation of Slc26a6 Mitigates Myocardial Ischemia/Reperfusion Injury.Biomedicines · 2025Article
- Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development.International journal of molecular sciences · 2025Review
- Regulation of Na/Ca exchange by cytoplasmic protons modifies intracellular calcium dynamics and the cardiac response to ischemia.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Identification of a magnesium-binding site at the primary allosteric calcium sensor of the sodium-calcium exchanger: Implications for physiological regulation.Protein science : a publication of the Protein Society · 2024Article
- Structural dynamics of NaCommunications biology · 2024Article
- Physiology of intracellular calcium buffering.Physiological reviews · 2023Review
- Structure-Based Function and Regulation of NCX Variants: Updates and Challenges.International journal of molecular sciences · 2022Review
- Proton-modulated interactions of ions with transport sites of prokaryotic and eukaryotic NCX prototypes.Cell calcium · 2021Article
- A guide to plasma membrane solute carrier proteins.The FEBS journal · 2021Review
- The Archaeal NaFrontiers in chemistry · 2021Review
- CALX-CBD1 CaBiophysical journal · 2020Article
- Dynamic Palmitoylation of the Sodium-Calcium Exchanger Modulates Its Structure, Affinity for Lipid-Ordered Domains, and Inhibition by XIP.Cell reports · 2020Article
- Modulation of the cardiac NaCell calcium · 2020Review
- Calcium Buffering in the Heart in Health and Disease.Circulation · 2019Review
- Key residues controlling bidirectional ion movements in NaCell calcium · 2018Article
- Molecular determinants of pH regulation in the cardiac NaThe Journal of general physiology · 2018Article
- Crosslink between calcium and sodium signalling.Experimental physiology · 2018Review
- Regional acidosis locally inhibits but remotely stimulates Ca2+ waves in ventricular myocytes.Cardiovascular research · 2017Article
- Modeling NaJournal of molecular and cellular cardiology · 2016Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
The cardiac Na(+)/Ca(2+) exchanger (NCX) regulates cellular [Ca(2+)](i) and plays a central role in health and disease, but its molecular regulation is poorly understood. Here we report on how protons affect this electrogenic transporter by modulating two critically important NCX C(2) regulatory domains, Ca(2+) binding domain-1 (CBD1) and CBD2. The NCX transport rate in intact cardiac ventricular myocytes was measured as a membrane current, I(NCX), whereas [H(+)](i) was varied using an ammonium chloride "rebound" method at constant extracellular pH 7.4. At pH(i) = 7.2 and [Ca(2+)](i) < 120 nM, I(NCX) was less than 4% that of its maximally Ca(2+)-activated value. I(NCX) increases steeply at [Ca(2+)](i) between 130-150 nM with a Hill coefficient (n(H)) of 8.0 ± 0.7 and K(0.5) = 310 ± 5 nM. At pH(i) = 6.87, the threshold of Ca(2+)-dependent activation of I(NCX) was shifted to much higher [Ca(2+)](i) (600-700 nM), and the relationship was similarly steep (n(H) = 8.0±0.8) with K(0.5) = 1042 ± 15 nM. The V(max) of Ca(2+)-dependent activation of I(NCX) was not significantly altered by low pH(i). The Ca(2+) affinities for CBD1 (0.39 ± 0.06 μM) and CBD2 (K(d) = 18.4 ± 6 μM) were exquisitely sensitive to [H(+)], decreasing 1.3-2.3-fold as pH(i) decreased from 7.2 to 6.9. This work reveals for the first time that NCX can be switched off by physiologically relevant intracellular acidification and that this depends on the competitive binding of protons to its C(2) regulatory domains CBD1 and CBD2.
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