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Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions

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Abstract

NCX proteins explore the electrochemical gradient of Na+ to mediate Ca2+-fluxes in exchange with Na+ either in the Ca2+-efflux (forward) or Ca2+-influx (reverse) mode, whereas the directionality depends on ionic concentrations and membrane potential. Mammalian NCX variants (NCX1-3) and their splice variants are expressed in a tissue-specific manner to modulate the heartbeat rate and contractile force, the brain’s long-term potentiation and learning, blood pressure, renal Ca2+ reabsorption, the immune response, neurotransmitter and insulin secretion, apoptosis and proliferation, mitochondrial bioenergetics, etc. Although the forward mode of NCX represents a major physiological module, a transient reversal of NCX may contribute to EC-coupling, vascular constriction, and synaptic transmission. Notably, the reverse mode of NCX becomes predominant in pathological settings. Since the expression levels of NCX variants are disease-related, the selective pharmacological targeting of tissue-specific NCX variants could be beneficial, thereby representing a challenge. Recent structural and biophysical studies revealed a common module for decoding the Ca2+-induced allosteric signal in eukaryotic NCX variants, although the phenotype variances in response to regulatory Ca2+ remain unclear. The breakthrough discovery of the archaebacterial NCX structure may serve as a template for eukaryotic NCX, although the turnover rates of the transport cycle may differ ∼103-fold among NCX variants to fulfill the physiological demands for the Ca2+ flux rates. Further elucidation of ion-transport and regulatory mechanisms may lead to selective pharmacological targeting of NCX variants under disease conditions.

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Abbreviations

CALX:

Drosophila melanogaster NCX ortholog

CAX:

Ca2+/anion exchanger

CBD:

Ca2+ binding domain

E Ca :

Equilibrium potential of Ca2+

E NCX :

Equilibrium potential of NCX

FRCRCFa:

NCX inhibitory cyclic hexapeptide

FRET:

Fluorescence resonance energy transfer.

I1-inactivation:

Na+-dependent inactivation of NCX

I2-inactivation:

Ca2+-dependent inactivation of NCX

NCLX:

Mitochondrial Na+/Ca2+ exchanger

NCKX:

Na+/Ca2+-K+ exchanger

NCX:

Na+/Ca2+ exchanger

n H :

Hill coefficient

NMR:

Nuclear magnetic resonance

SAXS:

Small-angle X-ray scattering

SLC8:

Solute carrier 8 gene family

SLC24:

Solute carrier 24 gene family

SR:

Sarcoplasmic reticulum

TM:

Trans-membrane segment

VCX:

Vacuolar Ca2+/H+ exchanger

LTCC:

L-type voltage-dependent Ca2+ channel

XIP:

NCX inhibitory peptide

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Acknowledgments

This work was supported by the Israeli Ministry of Health grant #2010-3-6266, the USA-Israeli Binational Research grant # 2009-334, and the Israel Science Foundation grant #23/10. Financial support from the Fields Foundation is highly appreciated.

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  1. Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, 69978, Israel

    Daniel Khananshvili

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In memoriam John Reeves

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Khananshvili, D. Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions. Pflugers Arch - Eur J Physiol 466, 43–60 (2014). https://doi.org/10.1007/s00424-013-1405-y

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