Sodium-Proton (Na(+)/H(+)) Antiporters: Properties and Roles in Health and Disease
- PMID:26860308
- DOI: 10.1007/978-3-319-21756-7_12
Sodium-Proton (Na(+)/H(+)) Antiporters: Properties and Roles in Health and Disease
Abstract
The transmembranal Na(+)/H(+) antiporters transport sodium (or several other monovalent cations) in exchange for H(+) across lipid bilayers in all kingdoms of life. They are critical in pH homeostasis of the cytoplasm and/or organelles. A particularly notable example is the SLC9 gene family, which encodes Na(+)/H(+) exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na(+)/H(+) antiporter is Ec-NhaA, the main Na(+)/H(+) antiporter of Escherichia coli.The crystal structure of down-regulated Ec-NhaA, determined at acidic pH, has provided the first structural insights into the antiport mechanism and pH regulation of an Na(+)/H(+) antiporter. It reveals a unique structural fold (called the NhaA fold) in which transmembrane segments (TMs) are organized in inverted-topology repeats, including two antiparallel unfolded regions that cross each other, forming a delicate electrostatic balance in the middle of the membrane. This unique structural fold (The NhaA fold) contributes to the cation binding site and facilitates the rapid conformational changes expected for Ec-NhaA. The NhaA fold has now been recognized to be shared by four Na(+)/H(+) antiporters (bacterial and archaeal) and a Na(+) symporter. Remarkably, no crystal structure of any of the human Na(+)/H(+) antiporters exists. Nevertheless, the Ec-NhaA crystal structure has enabled the structural modeling of NHE1, NHE9, and NHA2, three human plasmalemmal proteins that are members of the SLC9 family that are involved in human pathophysiology. Moreover, as outlined in this review, developments in the field, including cellular and biophysical methods that enable ion levels and fluxes to be measured in intact cells as well as in knockout mice, have led to striking advances in the identification and characterization of plasma membrane NHEs and NHA.Very little is known about the endomembrane isoforms of NHE. These intracellular exchangers may serve a function in cation homeostasis and/or osmoregulation, and not in pH regulation as is the case for the plasmalemmal isoforms. This intriguing possibility should be borne in mind when designing future studies. Future progress towards gaining an understanding of the SLC9 gene family, including its structure-function relationships and regulatory mechanisms in health and in disease, is likely to include insights into the pathophysiology of multiple diseases.
Keywords: Cation proton antiporter (CPA) superfamily; Membrane protein; NHA; NHE; Na+/H+ antiporter; NhaA; NhaA structural fold.
Similar articles
- NhaA crystal structure: functional-structural insights.Padan E, Kozachkov L, Herz K, Rimon A.Padan E, et al.J Exp Biol. 2009 Jun;212(Pt 11):1593-603. doi: 10.1242/jeb.026708.J Exp Biol. 2009.PMID:19448069Review.
- Functional and structural dynamics of NhaA, a prototype for Na(+) and H(+) antiporters, which are responsible for Na(+) and H(+) homeostasis in cells.Padan E.Padan E.Biochim Biophys Acta. 2014 Jul;1837(7):1047-62. doi: 10.1016/j.bbabio.2013.12.007. Epub 2013 Dec 19.Biochim Biophys Acta. 2014.PMID:24361841Review.
- Conformational changes in NhaA Na+/H+ antiporter.Kozachkov L, Padan E.Kozachkov L, et al.Mol Membr Biol. 2013 Feb;30(1):90-100. doi: 10.3109/09687688.2012.693209. Epub 2012 Jun 14.Mol Membr Biol. 2013.PMID:22694117
- Overexpression, Isolation, Purification, and Crystallization of NhaA.Padan E, Dwivedi M.Padan E, et al.Methods Enzymol. 2015;557:135-48. doi: 10.1016/bs.mie.2014.12.003. Epub 2015 Mar 17.Methods Enzymol. 2015.PMID:25950963
- The enlightening encounter between structure and function in the NhaA Na+-H+ antiporter.Padan E.Padan E.Trends Biochem Sci. 2008 Sep;33(9):435-43. doi: 10.1016/j.tibs.2008.06.007. Epub 2008 Aug 15.Trends Biochem Sci. 2008.PMID:18707888Review.
Cited by
- Genome-Assisted Probiotic Characterization and Application ofLactiplantibacillus plantarum 18 as a Candidate Probiotic for Laying Hen Production.Zhang G, Yang N, Liu Z, Chen X, Li M, Fu T, Zhang D, Zhao C.Zhang G, et al.Microorganisms. 2023 Sep 22;11(10):2373. doi: 10.3390/microorganisms11102373.Microorganisms. 2023.PMID:37894031Free PMC article.
- Reduced Nhe1 (Na+-H+ Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysms.Liu CL, Liu X, Wang Y, Deng Z, Liu T, Sukhova GK, Wojtkiewicz GR, Tang R, Zhang JY, Achilefu S, Nahrendorf M, Libby P, Wang X, Shi GP.Liu CL, et al.Hypertension. 2020 Jul;76(1):87-100. doi: 10.1161/HYPERTENSIONAHA.119.14485. Epub 2020 Jun 1.Hypertension. 2020.PMID:32475310Free PMC article.
- Incorporation of Barium Ions into Biomaterials: Dangerous Liaison or Potential Revolution?Kovrlija I, Locs J, Loca D.Kovrlija I, et al.Materials (Basel). 2021 Oct 2;14(19):5772. doi: 10.3390/ma14195772.Materials (Basel). 2021.PMID:34640168Free PMC article.Review.
- Ligand-induced conformational dynamics of theEscherichia coli Na+/H+ antiporter NhaA revealed by hydrogen/deuterium exchange mass spectrometry.Eisinger ML, Dörrbaum AR, Michel H, Padan E, Langer JD.Eisinger ML, et al.Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):11691-11696. doi: 10.1073/pnas.1703422114. Epub 2017 Oct 16.Proc Natl Acad Sci U S A. 2017.PMID:29078272Free PMC article.
- Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis.Chung CC, Lin YK, Chen YC, Kao YH, Yeh YH, Trang NN, Chen YJ.Chung CC, et al.Cardiovasc Diabetol. 2023 Feb 6;22(1):27. doi: 10.1186/s12933-023-01756-0.Cardiovasc Diabetol. 2023.PMID:36747205Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous