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The Na+/Ca2+ Exchanger Family: New Insights in Its Structure, Function, and Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (23 May 2023) | Viewed by 7241

Special Issue Editor

Dr. Moshe Giladi

E-Mail Website
Guest Editor
1. Department of Ophthalmology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
2. Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
Interests: sodium-calcium exchange; structure-function relationships; allosteric regulation; ion specificity; post-translational modifications; pharmacology

Special Issue Information

Dear Colleagues,

The Na+–Ca2+ exchanger (NCX) family plays a crucial role in maintaining cellular Ca2+ homeostasis throughout the kingdoms of life. Members of this family play key roles in a myriad of physiological processes, including skeletal and cardiac muscle activity, hormone secretion, neurotransmission, and renal function, among many more. While all NCX members share a common exchange mechanism, they greatly vary in their cellular localization, transport rates, exchange stoichiometry, ionic specificity, and regulatory mechanisms to orchestrate Ca2+ homeostasis in different tissues. Indeed, altered expression and regulation of NCX have been implicated in pathological processes such as heart failure, arrhythmia, and neurodegenerative disorders.

This Special Issue aims to provide a contemporary overview of NCX members’ function in health and disease, with a special focus on the underlying structure–function relationships and regulatory mechanisms. We encourage the submission of both review and original research articles addressing these topics, as well as manuscripts addressing the development of novel pharmacological approaches to target NCX in different disease states.

Dr. Moshe Giladi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sodium–calcium exchange
  • structure-function relationships
  • allosteric regulation
  • ion specificity
  • post-translational modifications
  • pharmacology

Published Papers (4 papers)

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Research

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17 pages, 3081 KiB  
Article
Inhibition of the Sodium–Calcium Exchanger Reverse Mode Activity Reduces Alcohol Consumption in Rats
by Gleice Kelli Silva-Cardoso and Prosper N’Gouemo
Int. J. Mol. Sci. 2024, 25(7), 4132; https://doi.org/10.3390/ijms25074132 - 8 Apr 2024
Viewed by 528
Abstract
Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play [...] Read more.
Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium–calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm. Initially, animals were trained to drink 7.5% ethanol and water for four weeks before administering SN-6 and KB-R7934. Afterward, their alcohol intake, preference, and water intake were recorded 2 and 24 h after exposure to water and 7.5% ethanol. SN-6 significantly reduced alcohol consumption by 48% in male and 36% in female rats without affecting their water intake. Additionally, SN-6 significantly reduced alcohol preference in females by 27%. However, KB-R7943 reduced alcohol consumption by 42% in female rats and did not affect alcohol preference or water intake. These findings suggest that alcohol exposure increased NCX reverse activity, and targeting NCX1 could be an effective strategy for reducing alcohol consumption in subjects susceptible to withdrawal seizures. Full article
(This article belongs to the Special Issue The Na+/Ca2+ Exchanger Family: New Insights in Its Structure, Function, and Regulation)
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12 pages, 1979 KiB  
Article
K+-Dependent Na+/Ca2+ Exchanger Isoform 2, Nckx2, Takes Part in the Neuroprotection Elicited by Ischemic Preconditioning in Brain Ischemia
by Ornella Cuomo, Rossana Sirabella, Francesca Boscia, Antonella Casamassa, Jonathan Lytton, Lucio Annunziato and Giuseppe Pignataro
Int. J. Mol. Sci. 2022, 23(13), 7128; https://doi.org/10.3390/ijms23137128 - 27 Jun 2022
Cited by 6 | Viewed by 1551
Abstract
Sodium/Calcium exchangers are neuronal plasma membrane antiporters which, by coupling Ca2+ and Na+ fluxes across neuronal membranes, play a relevant role in brain ischemia. The most brain-expressed isoform among the members of the K+-dependent Na+/Ca2+ exchanger [...] Read more.
Sodium/Calcium exchangers are neuronal plasma membrane antiporters which, by coupling Ca2+ and Na+ fluxes across neuronal membranes, play a relevant role in brain ischemia. The most brain-expressed isoform among the members of the K+-dependent Na+/Ca2+ exchanger family, NCKX2, is involved in the progression of the ischemic lesion, since both its knocking-down and its knocking-out worsens ischemic damage. The aim of this study was to elucidate whether NCKX2 functions as an effector in the neuroprotection evoked by ischemic preconditioning. For this purpose, we investigated: (1) brain NCKX2 expression after preconditioning and preconditioning + ischemia; (2) the contribution of AKT and calpain to modulating NCKX2 expression during preconditioning; and (3) the effect of NCKX2 knocking-out on the neuroprotection mediated by ischemic preconditioning. Our results showed that NCKX2 expression increased in those brain regions protected by ischemic preconditioning. These changes were p-AKT-mediated since its inhibition prevented NCKX2 up-regulation. More interestingly, NCKX2 knocking-out significantly prevented the protection exerted by ischemic preconditioning. Overall, our results suggest that NCKX2 plays a fundamental role in the neuroprotective effect mediated by ischemic preconditioning and support the idea that the enhancement of its expression and activity might represent a reasonable strategy to reduce infarct extension after stroke. Full article
(This article belongs to the Special Issue The Na+/Ca2+ Exchanger Family: New Insights in Its Structure, Function, and Regulation)
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Review

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19 pages, 1102 KiB  
Review
Regulation of K+-Dependent Na+/Ca2+-Exchangers (NCKX)
by Maryam Al-Khannaq and Jonathan Lytton
Int. J. Mol. Sci. 2023, 24(1), 598; https://doi.org/10.3390/ijms24010598 - 29 Dec 2022
Cited by 4 | Viewed by 2710
Abstract
Potassium-dependent sodium-calcium exchangers (NCKX) have emerged as key determinants of calcium (Ca2+) signaling and homeostasis, especially in environments where ion concentrations undergo large changes, such as excitatory cells and transport epithelia. The regulation of NCKX transporters enables them to respond to [...] Read more.
Potassium-dependent sodium-calcium exchangers (NCKX) have emerged as key determinants of calcium (Ca2+) signaling and homeostasis, especially in environments where ion concentrations undergo large changes, such as excitatory cells and transport epithelia. The regulation of NCKX transporters enables them to respond to the changing cellular environment thereby helping to shape the extent and kinetics of Ca2+ signals. This review examines the current knowledge of the different ways in which NCKX activity can be modulated. These include (i) cellular and dynamic subcellular location (ii); changes in protein expression mediated at the gene, transcript, or protein level (iii); genetic changes resulting in altered protein structure or expression (iv); regulation via changes in substrate concentration (v); and post-translational modification, partner protein interactions, and allosteric regulation. Detailed mechanistic understanding of NCKX regulation is an emerging area of research with the potential to provide important new insights into transporter function, the control of Ca2+ signals, and possible interventions for dysregulated Ca2+ homeostasis. Full article
(This article belongs to the Special Issue The Na+/Ca2+ Exchanger Family: New Insights in Its Structure, Function, and Regulation)
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34 pages, 3998 KiB  
Review
Structure-Based Function and Regulation of NCX Variants: Updates and Challenges
by Daniel Khananshvili
Int. J. Mol. Sci. 2023, 24(1), 61; https://doi.org/10.3390/ijms24010061 - 21 Dec 2022
Cited by 5 | Viewed by 1861
Abstract
The plasma-membrane homeostasis Na+/Ca2+ exchangers (NCXs) mediate Ca2+ extrusion/entry to dynamically shape Ca2+ signaling/in biological systems ranging from bacteria to humans. The NCX gene orthologs, isoforms, and their splice variants are expressed in a tissue-specific manner and exhibit [...] Read more.
The plasma-membrane homeostasis Na+/Ca2+ exchangers (NCXs) mediate Ca2+ extrusion/entry to dynamically shape Ca2+ signaling/in biological systems ranging from bacteria to humans. The NCX gene orthologs, isoforms, and their splice variants are expressed in a tissue-specific manner and exhibit nearly 104-fold differences in the transport rates and regulatory specificities to match the cell-specific requirements. Selective pharmacological targeting of NCX variants could benefit many clinical applications, although this intervention remains challenging, mainly because a full-size structure of eukaryotic NCX is unavailable. The crystal structure of the archaeal NCX_Mj, in conjunction with biophysical, computational, and functional analyses, provided a breakthrough in resolving the ion transport mechanisms. However, NCX_Mj (whose size is nearly three times smaller than that of mammalian NCXs) cannot serve as a structure-dynamic model for imitating high transport rates and regulatory modules possessed by eukaryotic NCXs. The crystal structures of isolated regulatory domains (obtained from eukaryotic NCXs) and their biophysical analyses by SAXS, NMR, FRET, and HDX-MS approaches revealed structure-based variances of regulatory modules. Despite these achievements, it remains unclear how multi-domain interactions can decode and integrate diverse allosteric signals, thereby yielding distinct regulatory outcomes in a given ortholog/isoform/splice variant. This article summarizes the relevant issues from the perspective of future developments. Full article
(This article belongs to the Special Issue The Na+/Ca2+ Exchanger Family: New Insights in Its Structure, Function, and Regulation)
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