Role of Genetic Mutations of the Na + /H + Exchanger Isoform 1, in Human Disease and Protein Targeting and Activity
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Role of Genetic Mutations of the Na+/H+ Exchanger Isoform 1, in Human Disease and Protein Targeting and Activity Larry Fliegel1 Received: 16 June 2020 / Accepted: 6 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The mammalian Na+/H+ exchanger isoform one (NHE1) is a plasma membrane protein that is ubiquitously present in human cells. It functions to regulate intracellular pH removing an intracellular proton in exchange for one extracellular sodium and is involved in heart disease and in promoting metastasis in cancer. It is made of a 500 amino acid membrane domain plus a 315 amino acid, regulatory cytosolic tail. The membrane domain is thought to have 12 transmembrane segments and a large membrane-associated extracellular loop. Early studies demonstrated that in mice, disruption of the NHE1 gene results in locomotor ataxia and a phenotype of slow-wave epilepsy. Defects included a progressive neuronal degeneration. Growth and reproductive ability were also reduced. Recent studies have identified human autosomal homozygous recessive mutations in the NHE1 gene (SLC9A1) that result in impaired development, ataxia and other severe defects, and explain the cause of the human disease Lichtenstein-Knorr syndrome. Other human mutations have been identified that are stop codon polymorphisms. These cause short non-functional NHE1 proteins, while other genetic polymorphisms in the NHE1 gene cause impaired expression of the NHE1 protein, reduced activity, enhanced protein degradation or altered kinetic activation of the protein. Since NHE1 plays a key role in many human physiological functions and in human disease, genetic polymorphisms of the protein that significantly alter its function and are likely play significant roles in varying human phenotypes and be involved in disease. Keywords Cerebellar ataxia · Lichtenstein-Knorr syndrome · Na+/H+ exchanger · NHE1 · Protein degradation · Protein mistargeting · SLC9A1 · Stop codon polymorphism
Introduction NHE1: Physiological and Pathological Roles The mammalian N a+/H+ exchanger isoform one (NHE1) is a plasma membrane protein ubiquitously expressed in human cells. It removes intracellular protons in exchange for one extracellular sodium ions with a one-to-one stoichiometry. NHE maintains intracellular pH ( pHi) neutral, which protects cells from acidification that occurs from metabolism. It also becomes more active in response to osmotic challenge, thereby regulating cell volume [1, 2]. There are ten different gene products that make up the ten isoforms of NHE. NHE1 * Larry Fliegel [email protected] 1
Department of Biochemistry, University Alberta, 347 Medical Sciences Building, Edmonton, AB T6G 2H7, Canada
is the first isoform discovered and is ubiquitous in mammals with several important physiological functions [3–9]. It is made of two domains, a membrane transport domain of 500 amino acids that moves ions and a cytosolic regulatory domain of 315 additional amino acids that functions to regulate the membrane domain [
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