Affinage

SLC9C1

Solute carrier family 9 member C1 · UniProt Q4G0N8

Length
1177 aa
Mass
135.2 kDa
Annotated
2026-04-28
100 papers in source corpus 1 papers cited in narrative 1 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9C1 encodes a sperm-specific Na+/H+ exchanger (sNHE) that is essential for human sperm motility and male fertility. A homozygous splicing mutation disrupting the cyclic nucleotide-binding domain of SLC9C1 causes asthenozoospermia and male infertility, with loss of protein expression confirmed in patient spermatozoa (PMID:33462806). SLC9C1 functions in intracellular pH homeostasis in sperm flagella and interacts with soluble adenylyl cyclase (sAC) to support capacitation signaling (PMID:33462806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2021 Medium

    Establishing that SLC9C1 is required for human sperm motility resolved whether the gene's function, previously characterized only in mice, is conserved and clinically relevant in humans.

    Evidence Whole-exome sequencing identified a homozygous splicing mutation in an infertile man with asthenozoospermia; RT-PCR, immunodetection, and immunofluorescence confirmed loss of SLC9C1 protein in patient sperm

    PMID:33462806

    Open questions at the time
    • Single patient in a single study; independent replication in additional families or cohorts is lacking
    • Direct ion transport activity of human SLC9C1 has not been measured in reconstituted or heterologous expression systems
    • The precise mechanism by which loss of the cyclic nucleotide-binding domain abolishes motility is undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical transport properties of human SLC9C1, the structural basis for cyclic nucleotide regulation of its exchanger activity, and the full spectrum of its interactors in the sperm flagellar signaling complex remain uncharacterized.
  • No electrophysiological or reconstitution data for human SLC9C1 Na+/H+ exchange activity
  • No structural model of the cyclic nucleotide-binding domain or its regulatory mechanism
  • Physical interaction with soluble adenylyl cyclase (sAC) has not been validated in human sperm

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 1
Pathway
R-HSA-1474165 Reproduction 1 R-HSA-382551 Transport of small molecules 1
Partners
ADCY10

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 SLC9C1 (sNHE), a sperm-specific Na+/H+ exchanger, is essential for human sperm motility. A homozygous splicing mutation (c.2748+2T>C) causing in-frame exon skipping and deletion within the cyclic nucleotide-binding domain of SLC9C1 was identified in an infertile man with asthenozoospermia. RT-PCR, immunodetection, and immunofluorescence on patient semen confirmed truncated/absent protein, establishing SLC9C1 as required for sperm motility, consistent with its mouse ortholog role in pH homeostasis and interaction with soluble adenylyl cyclase (sAC) in sperm signaling pathways. Whole-exome sequencing, RT-PCR, immunodetection, and immunofluorescence on patient semen samples; loss-of-function with defined phenotypic readout (asthenozoospermia/infertility) Clinical genetics Medium 33462806

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Cloning and sequencing of a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). The Journal of biological chemistry 338 1374392
1995 Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney international 322 8569082
1998 Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR). FEBS letters 241 9613608
1993 Heterologous expression and functional properties of amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the rat Na/H exchanger. The Journal of biological chemistry 224 8393860
2013 SLC9/NHE gene family, a plasma membrane and organellar family of Na⁺/H⁺ exchangers. Molecular aspects of medicine 216 23506868
1993 Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H+ exchanger isoform (NHE-2). The Journal of biological chemistry 213 7685025
1998 NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. The Journal of biological chemistry 206 9430655
1992 Immunocytochemical characterization of Na(+)-H+ exchanger isoform NHE-1 in rabbit kidney. The American journal of physiology 192 1279986
1991 Alpha-thrombin, epidermal growth factor, and okadaic acid activate the Na+/H+ exchanger, NHE-1, by phosphorylating a set of common sites. The Journal of biological chemistry 184 1655777
1993 Focal localization of the NHE-1 isoform of the Na+/H+ antiport: assessment of effects on intracellular pH. The EMBO journal 172 8262063
2013 NaV1.5 Na⁺ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia. Journal of cell science 139 23902689
2010 The c-MYC NHE III(1): function and regulation. Annual review of pharmacology and toxicology 136 19922264
1993 Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2). Proceedings of the National Academy of Sciences of the United States of America 128 7683411
1994 Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa. The American journal of physiology 127 8141271
2000 The B1 subunit of the H+ATPase is a PDZ domain-binding protein. Colocalization with NHE-RF in renal B-intercalated cells. The Journal of biological chemistry 123 10748165
1994 The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain. Biochemistry 123 8068684
2004 Characterization of the Bacillus cereus Nhe enterotoxin. Microbiology (Reading, England) 122 15583149
2015 Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. American journal of physiology. Renal physiology 115 25855513
1993 Glucocorticoid stimulation of ileal Na+ absorptive cell brush border Na+/H+ exchange and association with an increase in message for NHE-3, an epithelial Na+/H+ exchanger isoform. The Journal of biological chemistry 104 8380155
2016 A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1. Journal of the American Chemical Society 100 27669098
1999 cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor. The Journal of biological chemistry 99 10455146
2008 The role of NHE-1 in myocardial hypertrophy and remodelling. Journal of molecular and cellular cardiology 97 18329039
2021 Empagliflozin reduces oxidative stress through inhibition of the novel inflammation/NHE/[Na+]c/ROS-pathway in human endothelial cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 93 34896968
2003 Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes. Hypertension (Dallas, Tex. : 1979) 93 14610099
2002 H(2)O(2)-induced Ca(2+) overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway. American journal of physiology. Heart and circulatory physiology 91 12124207
2005 Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation 90 16216978
1994 ATP dependence of NHE-1, the ubiquitous isoform of the Na+/H+ antiporter. Analysis of phosphorylation and subcellular localization. The Journal of biological chemistry 90 8132605
2014 Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. The Journal of cell biology 88 24891603
2008 Bacillus cereus Nhe is a pore-forming toxin with structural and functional properties similar to the ClyA (HlyE, SheA) family of haemolysins, able to induce osmotic lysis in epithelia. Microbiology (Reading, England) 88 18310016
1995 Acid incubation increases NHE-3 mRNA abundance in OKP cells. The American journal of physiology 87 7631739
1998 Structure-function of recombinant Na/H exchanger regulatory factor (NHE-RF). The Journal of clinical investigation 84 9593775
1995 Hypertonic activation of AE2 anion exchanger in Xenopus oocytes via NHE-mediated intracellular alkalinization. The American journal of physiology 83 7840148
2004 Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition. American journal of physiology. Heart and circulatory physiology 82 14684366
2004 A mechanism for the activation of the Na/H exchanger NHE-1 by cytoplasmic acidification and mitogens. EMBO reports 82 14710192
1994 A unique sodium-hydrogen exchange isoform (NHE-4) of the inner medulla of the rat kidney is induced by hyperosmolarity. The Journal of biological chemistry 82 7961960
2010 Expression of mitochondrial fusion-fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition. Basic research in cardiology 78 20886221
2008 Intracellular ANG II directly induces in vitro transcription of TGF-beta1, MCP-1, and NHE-3 mRNAs in isolated rat renal cortical nuclei via activation of nuclear AT1a receptors. American journal of physiology. Cell physiology 75 18256274
1999 Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE-RF. The Journal of biological chemistry 75 10567424
1991 Structure of the 5'-flanking regulatory region and gene for the human growth factor-activatable Na/H exchanger NHE-1. The Journal of biological chemistry 72 2040601
2011 Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PloS one 71 22216126
2004 The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation. American journal of physiology. Gastrointestinal and liver physiology 66 14962844
1999 A mechanism for branchial acid excretion in marine fish: identification of multiple Na+/H+ antiporter (NHE) isoforms in gills of two seawater teleosts. The Journal of experimental biology 65 9882643
2013 The Bacillus cereus Hbl and Nhe tripartite enterotoxin components assemble sequentially on the surface of target cells and are not interchangeable. PloS one 64 24204713
1999 Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys. The American journal of physiology 64 10444581
2012 NHE-1: a promising target for novel anti-cancer therapeutics. Current pharmaceutical design 63 22360552
1996 Endothelin(B) receptor activates NHE-3 by a Ca2+-dependent pathway in OKP cells. The Journal of clinical investigation 63 8617878
2010 Ginseng inhibits cardiomyocyte hypertrophy and heart failure via NHE-1 inhibition and attenuation of calcineurin activation. Circulation. Heart failure 62 20971938
2007 DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. PLoS biology 61 17177603
2010 Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells. American journal of physiology. Renal physiology 59 20427472
2010 Bacillus cereus cytotoxins Hbl, Nhe and CytK are secreted via the Sec translocation pathway. BMC microbiology 59 21118484
2002 NHE blockade inhibits chemokine production and NF-kappaB activation in immunostimulated endothelial cells. American journal of physiology. Cell physiology 59 12107048
2005 The effect of environmental hypercapnia and salinity on the expression of NHE-like isoforms in the gills of a euryhaline fish (Fundulus heteroclitus). Journal of experimental zoology. Part A, Comparative experimental biology 58 15880778
1999 Dual mechanisms of regulation of Na/H exchanger NHE-3 by parathyroid hormone in rat kidney. The Journal of biological chemistry 58 10196218
2001 Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading. Kidney international 57 11703600
2002 Na+/H+ exchange activity and NHE-3 expression in renal tubules from the spontaneously hypertensive rat. Kidney international 55 12081574
2009 Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. Journal of molecular and cellular cardiology 53 19318234
2005 NHE-1-dependent intracellular sodium overload in hypertrophic hereditary cardiomyopathy: prevention by NHE-1 inhibitor. Journal of molecular and cellular cardiology 52 15808834
1997 Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney international 52 9083276
1995 Overexpression of csk inhibits acid-induced activation of NHE-3. Proceedings of the National Academy of Sciences of the United States of America 52 7541536
2012 Anti-proliferative effect of atrial natriuretic peptide on colorectal cancer cells: evidence for an Akt-mediated cross-talk between NHE-1 activity and Wnt/β-catenin signaling. Biochimica et biophysica acta 51 22387884
2010 Cytotoxicity of the Bacillus cereus Nhe enterotoxin requires specific binding order of its three exoprotein components. Infection and immunity 48 20624910
2002 Mechanisms of activation of NHE by cell shrinkage and by calyculin A in Ehrlich ascites tumor cells. The Journal of membrane biology 48 12202953
1999 Differential regulation of NHE isoforms by sodium depletion in proximal and distal segments of rat colon. The American journal of physiology 48 9950829
2020 Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1. Scientific reports 45 32242030
2001 Characterization of acute inhibition of Na/H exchanger NHE-3 by dopamine in opossum kidney cells. Kidney international 44 11135072
2007 Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition. Canadian journal of physiology and pharmacology 43 17612638
2001 Characterization of the Drosophila melanogaster alkali-metal/proton exchanger (NHE) gene family. The Journal of experimental biology 43 11719534
1995 Expression of the human sodium/proton exchanger NHE-1 in Xenopus laevis oocytes enhances sodium/proton exchange activity and establishes sodium/lithium countertransport. Pflugers Archiv : European journal of physiology 42 7603840
1997 Muscarinic agonists induce phosphorylation-independent activation of the NHE-1 isoform of the Na+/H+ antiporter in salivary acinar cells. The Journal of biological chemistry 41 8995260
2018 Genome-Wide Identification and Analysis of Arabidopsis Sodium Proton Antiporter (NHX) and Human Sodium Proton Exchanger (NHE) Homologs in Sorghum bicolor. Genes 40 29751546
1995 G alpha q and G alpha 13 regulate NHE-1 and intracellular calcium in epithelial cells. The American journal of physiology 40 7840138
1994 The cytoplasmic domain of the Na+/H+ exchangers (NHEs) dictates the nature of the hormonal response: behavior of a chimeric human NHE1/trout beta NHE antiporter. Proceedings of the National Academy of Sciences of the United States of America 40 8202503
2021 The sodium/proton exchanger SLC9C1 (sNHE) is essential for human sperm motility and fertility. Clinical genetics 39 33462806
1996 Cellular distribution and regulation of NHE-1 isoform of the NA-H exchanger in the avian osteoclast. Bone 39 8833201
2012 An inhibitor of Na(+)/H(+) exchanger (NHE), ethyl-isopropyl amiloride (EIPA), diminishes proliferation of MKN28 human gastric cancer cells by decreasing the cytosolic Cl(-) concentration via DIDS-sensitive pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 36 23075671
2003 Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1). Cardiovascular drug reviews 36 12595915
2008 Estrogen exerts concentration-dependent pro-and anti-hypertrophic effects on adult cultured ventricular myocytes. Role of NHE-1 in estrogen-induced hypertrophy. Journal of molecular and cellular cardiology 35 19111554
1998 Colitis-induced changes in the expression of the Na+/H+ exchanger isoform NHE-1. The Journal of pharmacology and experimental therapeutics 35 9580638
2014 Physiological cardiac hypertrophy: critical role of AKT in the prevention of NHE-1 hyperactivity. Journal of molecular and cellular cardiology 34 25240639
2001 NHE and ICAM-1 expression in hypoxic/reoxygenated coronary microvascular endothelial cells. American journal of physiology. Heart and circulatory physiology 34 11356638
2008 Early signals after stretch leading to cardiac hypertrophy. Key role of NHE-1. Frontiers in bioscience : a journal and virtual library 33 18508719
2006 Cytotoxic mechanisms of Zn2+ and Cd2+ involve Na+/H+ exchanger (NHE) activation by ROS. Aquatic toxicology (Amsterdam, Netherlands) 33 16737744
1996 Glucocorticoids regulate NHE-3 transcription in OKP cells. The American journal of physiology 33 8769835
1994 Proximal regulatory elements and nuclear activities required for transcription of the human Na+/H+ exchanger (NHE-1) gene. Biochimica et biophysica acta 33 8286417
1993 Cytosolic pH sensitivity of an expressed human NHE-1 Na(+)-H+ exchanger. The American journal of physiology 33 8476023
2013 Complex formation between NheB and NheC is necessary to induce cytotoxic activity by the three-component Bacillus cereus Nhe enterotoxin. PloS one 32 23646182
2007 Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2. Clinical and experimental pharmacology & physiology 32 18177483
1999 HCO-3 reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response. The American journal of physiology 32 10362780
1994 Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA levels in human lymphocytes during metabolic acidosis. The American journal of physiology 31 7511337
2020 Empagliflozin Decreases Lactate Generation in an NHE-1 Dependent Fashion and Increases α-Ketoglutarate Synthesis From Palmitate in Type II Diabetic Mouse Hearts. Frontiers in cardiovascular medicine 29 33344518
1995 Parathyroid hormone and parathyroid hormone-related peptide activate the Na+/H+ exchanger NHE-1 isoform in osteoblastic cells (UMR-106) via a cAMP-dependent pathway. The Journal of biological chemistry 29 7559463
1994 Localization of the Na+/H+ exchanger isoform NHE-3 in rabbit and canine kidney. Biochimica et biophysica acta 29 7918570
2018 Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity. Acta physiologica (Oxford, England) 28 31595734
2011 Bicarbonate, NBCe1, NHE, and carbonic anhydrase activity enhance lactate-H+ transport in bovine corneal endothelium. Investigative ophthalmology & visual science 28 21896839
1998 The myocardial sodium-hydrogen exchanger (NHE) and its role in mediating ischemic and reperfusion injury. The Keio journal of medicine 28 9659815
1995 Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA expression in lymphocytes from patients with essential hypertension. Hypertension (Dallas, Tex. : 1979) 28 7875760
2011 In vivo key role of reactive oxygen species and NHE-1 activation in determining excessive cardiac hypertrophy. Pflugers Archiv : European journal of physiology 27 21870055
2008 Late expression of Na+/H+ exchanger 1 (NHE1) and neuroprotective effects of NHE inhibitor in the gerbil hippocampal CA1 region induced by transient ischemia. Experimental neurology 27 18511042
2004 Endotoxin differentially modulates the basolateral and apical sodium/proton exchangers (NHE) in enterocytes. Surgery 27 15300204
1998 Mechanisms of pH preservation during global ischemia in preconditioned rat heart: roles for PKC and NHE. The American journal of physiology 27 9724283