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

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• 作者：Daniel Khananshvili (1)
  
• 关键词：NCX ; Antiporter ; Structure–activity relationships ; Tissue ; specific regulation ; Alternating access ; Catalytic capacity ; Sodium ; Calcium
• 刊名：Pfl篓鹿gers Archiv - European Journal of Physiology
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：466
• 期：1
• 页码：43-60
• 全文大小：747 KB
• 作者单位：Daniel Khananshvili (1)
  
  1. Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, 69978, Israel
  
• ISSN：1432-2013

文摘

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 ?03-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.