Prof. Daniel Khananshvili

Emeritus in Physiology Pharmacology
פיזיולוגיה ופרמקולוגיה אמריטוס
Prof. Daniel Khananshvili
Phone: 03-6409961
Fax: 03-6409113
Office: Sackler School of Medicine, 5


Associate Professor, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University





Postdoctoral Research in Ion-transport Mechanisms and Enzymology

Brandeis University, Waltham, USA
1980-1986 Ph.D in Biochemistry and Bioenergetics The Weizmann Institute of Science, Rehovot, Israel
1976-1979 M.Sc in Biochemistry and Neurochemistry University of Tbilisi, Georgia, former USSR

B.Sc in Chemistry and Biology

University of Tbilisi, Georgia, former USSR



Mechanisms, Regulation and Pharmacology of Calcium Transporting NCX Proteins

Calcium (Ca2+) is a major regulator in the living cell. In many cell-types the Na+/Ca2+ exchanger proteins (NCX) represent a major Ca2+ extruding system and thus, play a key role in regulating the Ca2+-dependent events in the cell. Three NCX genes form numerous splice variants, which are expressed in a tissue-specific manner to regulate excitation–contraction coupling in heart, long-term potentiation and learning in brain, blood pressure, immune responses, neurotransmitter and hormone secretion, kidney Ca2+ reabsorption, mitochondrial bioenergetics, etc. Altered expression and regulation of NCX proteins is a chief contributor to Ca2+-driven tissue-remodeling in heart failure, cerebral ischemia, hypertension, diabetes, renal malfunction, muscle dystrophy, etc. For example, in cardiac disease a single isoform/splice variant (NCX1.1) is overexpressed, thereby representing a primary concern for life-threating arrhythmias and contractile malfunction. Selective pharmacological targeting of NCX variants is expected to recover Ca2+ homeostasis in predefined cell types and thus, may improve desired activity of altered tissues/organs.


Since this breakthrough remains challenging our research efforts are focused on two principle issues: a) To resolve structure-activity relationships underlying the function and regulation of diverse NCX variants; b) To develop new experimental approaches for selective pharmacological targeting of tissue-specific NCX variants with a goal of providing new opportunities for preventing and effective treatment of harmful diseases. In this respect we investigate structure-activity relationships in the wild-type and mutated proteins by exploring a wide spectrum of techniques (stopped-flow and ion-flux assays, FRET, SAXS, ITC, X-ray crystallography, confocal microscopy, patch-clamp, etc). In searching the regulatory mechanisms of CBD1 and CBD2 domains we found that the tissue-specific splice segment, located on CBD2, shapes the regulatory specificity of the primary Ca2+ sensor located on CBD1. These findings may allow the identification of drug candidates targeting the disease-related NCX variants.


Publications & Grants


Marinelli F, Almagor L, Hiller R, Giladi M, Khananshvili D*, and Faraldo-Gómez JD. Sodium recognition by the Na+/Ca2+ exchanger in the outward-facing conformation. (*Corresponding Author). Proc Natl Acad Sci USA, 2014, doi:10.1073/pnas.1415751111


Giladi M, Lee S-Y, Hiller R, Chung K-Y, and Khananshvili, D. Structure-dynamic determinants governing a mode of regulatory response and propagation of allosteric signal in splice variants of Na+/Ca2+ exchange (NCX) proteins. Biochem J, doi:10.1042/BJ20141036


Almagor L, Giladi M, van Dijk L, Buki T, Hiller R, and Khananshvili D. Functional asymmetry of bidirectional ca2+-movements in an archaeal sodium-calcium exchanger (NCX_Mj). Cell Calcium 2014, 56:276-284.


Giladi M, Michaely L, Almagor A, Bar-On D, Buki T, Ashery U, Khananshvili, Hirsch JA. The C2B domain is the primary Ca2+ sensor in DOC2B: A structural and functional analysis. J Mol Biol, 2013, 425:4629–4641.


Giladi M, Hiller R, Hirsch JA, Khananshvili D. Population shift underlies Ca2+-induced regulatory transitions in the sodium-calcium exchanger (NCX). J Biol Chem, 2013, 288:23141-23149.


Giladi, M. and Khananshvili, D. Molecular determinants of allosteric regulation in NCX proteins. Adv Exp Med and Biol, 2013, 961:35-48.


Khananshvili D, Binah O, Attali B. The Ca2+-activated K+ channel IKCa/SK4: a critical new player in human embryonic cardiac pacemaker. Proc Natl Acad Sci USA, 2013, 110:1685-1694.


Nita II, Hershfinkel M, Fishman D, Ozeri E, Rutter GA, Sensi SL, Khananshvili D, Lewis EC, Sekler I. The mitochondrial Na+/Ca2+ exchanger upregulates glucose dependent Ca2+ signaling linked to insulin secretion. PloS One 2012, 7:e46649.


Giladi M, Friedberg I, Fang X, Hiller R, Wang YX, Khananshvili D. G503 is obligatory for coupling of regulatory domains in NCX proteins. Biochemistry 2012, 51:7313-720.


Giladi, M., Bohbot, H., Buki, T., Schulze, D. H., Hiller, R. and Khananshvili, D. Dynamic features of allosteric Ca2+ sensor in tissue-specific NCX variants. Cell Calcium, 51:478-485, 2012.


Giladi M, Sasson Y, Fang X, Hiller R, Buki T, Wang Y-X, Hirsch JA and Khananshvili D. A common Ca2+-driven interdomain module governs eukaryotic NCX regulation. PloS One, 7:e39985. 2012


Boyman L, Hagen BM, Giladi M, Hiller R, WJ Lederer and Khananshvili D. Proton-Sensing Ca2+ Binding Domains Regulate the Cardiac Na+/Ca2+ Exchanger. J Biol Chem, 286:28811-28820, 2011. 


Giladi M, Boyman L, Mikhasenko H, Hiller R and Khananshvili D. Essential role of the CBD1-CBD2 linker in slow dissociation of Ca2+ from the regulatory two-domain tandem of NCX1. J BiolChem 285:28117–28125, 2010.


Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman, D., Shoshan-Barmatz V, Herrmann S, Khananshvili D and Sekler I. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci USA 107:436-441, 2010.




Khananshvili, D. Sodium-Calcium Exchangers (NCX): Molecular Hallmarks Underlying Tissue-Specific and Systemic Functions, Pflügers Arch (in press)


Khananshvili, D. SLC8 gene family of sodium-calcium exchangers (NCX): Structure, function and regulation in health and disease. Mol Asp Med 34:220-35, 2013.


Giladi, M. and Khananshvili, D. (2013) Molecular determinants of allosteric regulation in NCX proteins. Adv Exp Med Biol 961:35-48.


Boyman L, GSB Williams, Khananshvili D, Sekler I, WJ Lederer. NCLX: The mitochondrial sodium calcium exchanger. J Mol Cell Cardiology 2013, 59:205-213.




2013-2017       Fields Center of Molecular Cardiology

2010-2015       USA-Israel Binational Science Foundation   

2014-2018       Israeli Science Foundation    


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