Editing Israel Hanukoglu (section)

===Epithelial sodium channel (ENaC)===

In his clinical work as an endocrinologist, Israel's older brother, Prof. [[Aaron Hanukoglu]] ([[Tel Aviv University]], Sackler Medical School and E. Wolfson Medical Center), identified that a hereditary disease named pseudohypoaldosteronism (PHA) type I encompasses two independent syndromes.<ref name="1991-Hanukoglu" >{{cite journal | vauthors = Hanukoglu A | title = Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 73 | issue = 5 | pages = 936–44 | date = November 1991 | pmid = 1939532 | doi = 10.1210/jcem-73-5-936 | url = https://zenodo.org/record/890914 }}</ref> Following this discovery the two brothers continued their collaboration to understand the molecular basis of the severe form of PHA.

By their collaborative work that also included additional labs, the Hanukoglu brothers discovered that the severe forms of pseudohypoaldosteronism type I result from mutations in three genes ([[SCNN1A]], [[SCNN1B]], and [[SCNN1B]]) that encode for protein subunits of the Epithelial sodium (Na<sup>+</sup>) channel (ENaC).<ref name="pmid8824886">{{cite journal | vauthors = Strautnieks SS, Thompson RJ, Hanukoglu A, Dillon MJ, Hanukoglu I, Kuhnle U, Seckl J, Gardiner RM, Chung E | title = Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping | journal = Human Molecular Genetics | volume = 5 | issue = 2 | pages = 293–9 | date = February 1996 | pmid = 8824886 | doi = 10.1093/hmg/5.2.293 | doi-access = free }}</ref><ref name="pmid8589714">{{cite journal | vauthors = Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP | title = Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1 | journal = Nature Genetics | volume = 12 | issue = 3 | pages = 248–53 | date = March 1996 | pmid = 8589714 | doi = 10.1038/ng0396-248 | s2cid = 8185511 }}</ref><ref name="pmid12107247">{{cite journal | vauthors = Saxena A, Hanukoglu I, Saxena D, Thompson RJ, Gardiner RM, Hanukoglu A | title = Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 7 | pages = 3344–50 | date = July 2002 | pmid = 12107247 | doi = 10.1210/jcem.87.7.8674 | doi-access = free }}</ref><ref name="pmid15853823">{{cite journal | vauthors = Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A | title = Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism | journal = Clinical Endocrinology | volume = 62 | issue = 5 | pages = 547–53 | date = May 2005 | pmid = 15853823 | doi = 10.1111/j.1365-2265.2005.02255.x | s2cid = 2749562 }}</ref> These studies also helped establish that ENaC is the principal channel involved in blood volume and blood pressure regulation in humans.<ref name="2016-Hanukoglu" >{{cite journal | vauthors = Hanukoglu I, Hanukoglu A | title = Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases | journal = Gene | volume = 579 | issue = 2 | pages = 95–132 | date = April 2016 | pmid = 26772908 | pmc = 4756657 | doi = 10.1016/j.gene.2015.12.061 }}</ref>

Following these studies, the Hanukoglu brothers directed their attention to understand the structure and function of ENaC assembled from normal and mutated subunits. Their analyses showed that the phenotypic variations in the severity of pseudohypoaldosteronism are associated with the types of genetic mutations.<ref>{{cite journal | vauthors = Hanukoglu A, Edelheit O, Shriki Y, Gizewska M, Dascal N, Hanukoglu I | title = Renin-aldosterone response, urinary Na/K ratio and growth in pseudohypoaldosteronism patients with mutations in epithelial sodium channel (ENaC) subunit genes | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 111 | issue = 3–5 | pages = 268–74 | date = September 2008 | pmid = 18634878 | doi = 10.1016/j.jsbmb.2008.06.013 | s2cid = 24688546 }}</ref><ref>{{cite journal | vauthors = Edelheit O, Hanukoglu I, Shriki Y, Tfilin M, Dascal N, Gillis D, Hanukoglu A | title = Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 119 | issue = 1–2 | pages = 84–8 | date = March 2010 | pmid = 20064610 | doi = 10.1016/j.jsbmb.2010.01.002 | s2cid = 9564777 }}</ref> Their work on the structure of ENaC subunits led to the identification of charged residues and regions responsible for transport of the protein to membrane and for regulation of extracellular Na<sup>+</sup> ions.<ref name="2011-Edelheit">{{cite journal | vauthors = Edelheit O, Hanukoglu I, Dascal N, Hanukoglu A | title = Identification of the roles of conserved charged residues in the extracellular domain of an epithelial sodium channel (ENaC) subunit by alanine mutagenesis | journal = American Journal of Physiology. Renal Physiology | volume = 300 | issue = 4 | pages = F887-97 | date = April 2011 | pmid = 21209000 | doi = 10.1152/ajprenal.00648.2010 | s2cid = 869654 }}</ref><ref name="2014-Edelheit">{{cite journal | vauthors = Edelheit O, Ben-Shahar R, Dascal N, Hanukoglu A, Hanukoglu I | title = Conserved charged residues at the surface and interface of epithelial sodium channel subunits--roles in cell surface expression and the sodium self-inhibition response | journal = The FEBS Journal | volume = 281 | issue = 8 | pages = 2097–111 | date = April 2014 | pmid = 24571549 | doi = 10.1111/febs.12765 | s2cid = 5807500 | doi-access = free }}</ref>

In an extensive review of studies on ASIC and ENaC, Prof. Hanukoglu has summarized the major similarities between [[ASIC]] and ENaC type channels.<ref>{{cite journal | vauthors = Hanukoglu I | title = ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters | journal = The FEBS Journal | volume =  284| issue =  4| pages = 525–545 | date = August 2016 | pmid = 27580245 | doi = 10.1111/febs.13840 | s2cid = 24402104 | url = https://zenodo.org/record/890906 }}</ref>

To define the sites of localization of ENaC in tissues and within cells, Hanukoglu's laboratory generated polyclonal antibodies against extracellular ENaC subunits. These antibodies for the first time permitted visualization of intracellular localization of ENaC at high resolution and led to the discovery that in all cells with motile cilia ENaC is located on cilia.<ref name="pmid22207244">{{cite journal | vauthors = Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A | title = Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways | journal = Histochemistry and Cell Biology | volume = 137 | issue = 3 | pages = 339–53 | date = March 2012 | pmid = 22207244 | doi = 10.1007/s00418-011-0904-1 | s2cid = 15178940 }}</ref> These studies establish that ENaC is an important regulator of fluid level in the luminal side of cells with motile cilia in the female reproductive and respiratory tract.<ref name="pmid22207244" /> More recently, they showed that these sodium channels are also located in the seminiferous tubules in the testis and in the tail and head region of sperm.<ref name="Sharma-2018">{{cite journal|vauthors=Sharma S, Hanukoglu A, Hanukoglu I | title=Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa. | journal=Journal of Molecular Histology | year= 2018 | volume= 49 | issue= 2 | pages= 195–208 | pmid=29453757 | doi=10.1007/s10735-018-9759-2 | s2cid=3761720 }}</ref>

Systemic pseudohypoaldosteronism patients with mutated ENaC subunits may lose significant amount salt in sweat especially at hot climates.<ref name="1991-Hanukoglu" /> To identify the sites of salt loss, Hanukoglu brothers examined the localization of ENaC in the human skin.<ref name="2017-Hanukoglu-2">{{cite journal | vauthors = Hanukoglu I, Boggula VR, Vaknine H, Sharma S, Kleyman T, Hanukoglu A | title = Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages | journal = Histochemistry and Cell Biology | volume = 147 | issue = 6 | pages = 733–748 | date = January 2017 | pmid = 28130590 | doi = 10.1007/s00418-016-1535-3 | s2cid = 8504408 |url=https://zenodo.org/record/890756}}</ref> In a comprehensive study examining all the layers of skin and epidermal appendages, they found a widespread distribution of ENaC in keratinocytes in the epidermal layers. Yet, in the eccrine sweat glands, ENaC was localized on the apical cell membrane exposed to the duct of these sweat glands. Based on additional observations, they concluded that the ENaC located on the eccrine gland sweat ducts is responsible for the uptake of Na<sup>+</sup> ions from sweat secretions. This recycling of Na<sup>+</sup> reduces the concentration of salt in perspiration and prevents the loss of salt at hot climates via [[perspiration]].<ref name="2017-Hanukoglu-2" />