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

Daniel Khananshvili*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


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 ∼10 3-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.

Original languageEnglish
Pages (from-to)43-60
Number of pages18
JournalPflugers Archiv European Journal of Physiology
Issue number1
StatePublished - Jan 2014


  • Alternating access
  • Antiporter
  • Calcium
  • Catalytic capacity
  • NCX
  • Sodium
  • Structure-activity relationships
  • Tissue-specific regulation


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