title: Alternative splicing of NHE-1 mediates Na-Li countertransport and associates with activity rate.
abstract: Sodium-lithium countertransport (SLC) is an ouabain-insensitive exchange of Na for Li found in the erythrocyte membrane of several mammalian species. Although increased SLC activity is presently the most consistent intermediate phenotype of essential hypertension and diabetic nephropathy in humans, the gene responsible for this membrane transport has not been identified. Because of functional similarities, SLC was suggested to represent an in vitro mode of operation of the Na-H exchanger (NHE). This hypothesis, however, has been long hampered by the total insensitivity of SLC to amiloride, which is an intrinsic inhibitor of the first isoform of NHE, the only NHE isoform detected in human erythrocytes. We describe here the identification in human reticulocytes and erythrocytes of an alternative splicing of NHE lacking the amiloride binding site. Transfection experiments with this spliced variant restore amiloride-insensitive, phloretin-sensitive SLC activity. Expression of both regular and spliced transcripts of NHE is increased in subjects with high SLC activity. Altogether, these findings, by extending to NHE the characteristics of inheritance and predictivity previously attributed to SLC, eventually restore the candidacy of NHE isoform 1 as a gene involved in the pathogenesis of essential hypertension and diabetic nephropathy.
authors.affiliation: Renal Pathophysiology Laboratory, Division of Medicine, San Raffaele Scientific Institute, Via Olgettina 60, I-20132 Milan, Italy. g.zerbini@hsr.it
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Anna
authors.initials: A
authors.lastname: Maestroni
authors.forename: Diego
authors.initials: D
authors.lastname: Breviario
authors.forename: Ruggero
authors.initials: R
authors.lastname: Mangili
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D017920:Antiporters / Q000097:blood*; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008094:Lithium / Q000097:blood; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010693:Phloretin / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D012964:Sodium / Q000097:blood; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D017920:Antiporters; D017931:DNA Primers; D011994:Recombinant Proteins; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C045885:sodium-lithium countertransporter; D008094:Lithium; D012964:Sodium; D010693:Phloretin