TY - JOUR
T1 - Sodium-calcium exchangers (NCX)
T2 - Molecular hallmarks underlying the tissue-specific and systemic functions
AU - Khananshvili, Daniel
N1 - Funding Information:
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.
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
KW - Alternating access
KW - Antiporter
KW - Calcium
KW - Catalytic capacity
KW - NCX
KW - Sodium
KW - Structure-activity relationships
KW - Tissue-specific regulation
UR - http://www.scopus.com/inward/record.url?scp=84891860933&partnerID=8YFLogxK
U2 - 10.1007/s00424-013-1405-y
DO - 10.1007/s00424-013-1405-y
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AN - SCOPUS:84891860933
SN - 0031-6768
VL - 466
SP - 43
EP - 60
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
IS - 1
ER -