{"gene":"SLC41A1","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2005,"finding":"Mouse SLC41A1 expressed in Xenopus laevis oocytes mediates saturable, rheogenic, voltage-dependent Mg2+ uptake (Km ~0.67 mM) that is not coupled to Na+ or Cl-, and also transports Sr2+, Zn2+, Cu2+, Fe2+, Co2+, Ba2+, and Cd2+; La3+ abolishes uptake. The transcript is upregulated in kidney with Mg2+ deficiency.","method":"Two-electrode voltage-clamp in Xenopus oocytes expressing cloned mouse SLC41A1","journal":"Physiological genomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro electrophysiology with kinetic characterization, single lab but multiple ionic substitution controls and saturation kinetics","pmids":["15713785"],"is_preprint":false},{"year":2008,"finding":"Human SLC41A1 overexpressed in HEK293 cells localizes to the plasma membrane, forms high-molecular-mass protein complexes, mediates Mg2+ efflux (reducing free and total intracellular Mg2+), is temperature-sensitive, and is insensitive to cobalt(III) hexaammine. It functionally complements a Salmonella enterica strain lacking all three endogenous Mg2+ transport systems (CorA, MgtA, MgtB), confirming it as a bona fide Mg2+ carrier.","method":"Genetic complementation in Mg2+-transport-deficient Salmonella; whole-cell patch clamp in HEK293; intracellular Mg2+ measurements (mag-fura-2 fluorescence); subcellular fractionation/Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (complementation, patch clamp, fluorescent Mg2+ assay, membrane localization) in a single rigorous study","pmids":["18367447"],"is_preprint":false},{"year":2011,"finding":"Human SLC41A1 overexpressed in HEK293 cells mediates Na+-dependent Mg2+ efflux; a 3–9-fold elevation of intracellular Mg2+ drives 5–9-fold increased efflux strictly dependent on extracellular Na+ (91% abolished by N-methyl-D-glucamine replacement). Known Na+/Mg2+ exchanger inhibitors imipramine and quinidine inhibited efflux by 88–100%. Transport activity is regulated by cAMP-dependent protein kinase A (PKA) phosphorylation.","method":"Fluorescent Mg2+ probe (mag-fura-2) in SLC41A1-overexpressing HEK293 cells; ionic substitution; pharmacological inhibition; PKA stimulation","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (ionic substitution, pharmacology, kinase stimulation) in a single focused study establishing Na+/Mg2+ exchanger identity and PKA regulation","pmids":["22031603"],"is_preprint":false},{"year":2011,"finding":"SLC41A1 Mg2+ transport function is regulated post-transcriptionally by extracellular Mg2+ via an N-terminal cytoplasmic domain-dependent endosomal recycling mechanism. The N-terminal domain is required for Mg2+-dependent regulation of lysosomal degradation and plasma membrane surface expression. SLC41A1 adopts the same plasma membrane topology as bacterial MgtE, and an intact Mg2+-transporting pore is required to complement growth of TRPM7-deficient cells.","method":"Structure-function analysis with truncation/domain mutants; complementation of TRPM7-deficient DT40 B-cells; subcellular localization studies; surface expression assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple complementary experiments (complementation, localization, domain mutagenesis, surface expression) in a single study","pmids":["21696366"],"is_preprint":false},{"year":2013,"finding":"A homozygous splice-acceptor mutation (c.698G>T) in SLC41A1 causing in-frame skipping of exon 6 (deletion of a transmembrane helix) completely abolishes the protein's Mg2+ transport function. In normal human kidney, endogenous SLC41A1 localizes specifically to renal tubules at the corticomedullary boundary. Morpholino knockdown of slc41a1 in zebrafish produces ventral body curvature, hydrocephalus, and cystic kidneys similar to nephronophthisis (NPHP) gene knockdowns.","method":"Transfection of WT vs. exon-6-deleted mutant SLC41A1 with functional transport assay; immunolocalization in human kidney tissue; morpholino knockdown in zebrafish","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutation with direct transport assay, tissue localization, and in vivo zebrafish phenotype all in one study","pmids":["23661805"],"is_preprint":false},{"year":2013,"finding":"The PD-associated substitution p.A350V in SLC41A1 is a gain-of-function mutation that enhances Na+-dependent Mg2+ efflux by ~69% compared to wild-type. This enhanced efflux capacity is accompanied by insensitivity of the mutant to cAMP/PKA stimulation, indicating disrupted hormonal regulation, and results in reduced cell proliferation.","method":"Fluorescent Mg2+ efflux assay (mag-fura-2) in HEK293 cells expressing WT or p.A350V SLC41A1; PKA stimulation; proliferation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional transport assay with mutant vs. WT comparison and PKA regulation experiment; single lab","pmids":["23976986"],"is_preprint":false},{"year":2013,"finding":"SLC41A1 membrane topology was experimentally determined to have both N- and C-termini oriented intracellularly, consistent with a 10 transmembrane helix model, using split-ubiquitin yeast two-hybrid assays with orientation-specific membrane marker co-expression.","method":"Split-ubiquitin functional assay in S. cerevisiae with C- or N-terminally tagged SLC41A1 fused to Cub-LexA-VP16 reporter, co-expressed with NubI-tagged orientation markers","journal":"Magnesium research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct topology assay in yeast, single lab, single method","pmids":["24491491"],"is_preprint":false},{"year":2013,"finding":"Using split-ubiquitin yeast two-hybrid screening, putative binding partners of SLC41A1 were identified, including 3-beta-hydroxysteroid-Δ8,Δ7-isomerase, BAP31 (BCAP31), IER3IP1, PPIB, and others mostly localized to the ER, suggesting they contribute to SLC41A1 maturation, folding, and anterograde transport. Co-purification with strep-tagged SLC41A1 identified ACCA1, UBB, ATX2L, HSP7C, and TBB as co-purifying proteins.","method":"Split-ubiquitin yeast two-hybrid assay; co-purification with strep-tagged SLC41A1 followed by mass spectrometry","journal":"Magnesium research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Y2H screen without confirmatory Co-IP validation; no interactor confirmed by mass spectrometry from the Y2H hits; single lab","pmids":["23823179"],"is_preprint":false},{"year":2014,"finding":"SLC41A1 knockdown by siRNA in cardiac fibroblasts attenuates angiotensin II-induced Mg2+ efflux, prevents the associated rise in intracellular Ca2+, reduces NFATc4 nuclear translocation, and suppresses upregulation of fibrosis markers (CTGF, fibronectin, α-SMA), identifying SLC41A1-mediated Mg2+ extrusion as upstream of Ca2+-NFATc4 fibrogenic signaling.","method":"siRNA knockdown of SLC41A1 in cardiac fibroblasts; intracellular Mg2+ and Ca2+ measurements; Western blot for fibrosis markers; NFATc4 nuclear translocation assay","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with multiple downstream readouts placing SLC41A1 in a signaling pathway; single lab","pmids":["25263961"],"is_preprint":false},{"year":2014,"finding":"The R244H variant of SLC41A1, identified in an early-onset PD patient, produces a loss-of-function in Mg2+ efflux when expressed in HEK293 cells, while the protein still co-localizes to plasma membrane regions (wheat germ agglutinin-positive areas) similar to wild-type.","method":"Stable expression of WT vs. R244H SLC41A1 in HEK293 cells; mag-fluo-4 fluorescent Mg2+ efflux assay; immunofluorescence co-localization with WGA","journal":"Parkinsonism & related disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay of variant vs. WT with localization confirmation; single lab, single method per endpoint","pmids":["24661466"],"is_preprint":false},{"year":2015,"finding":"Insulin inhibits SLC41A1-mediated Mg2+ efflux by up to ~51% via the insulin-signaling pathway (ISP); this inhibition is reversed by ISP inhibitors wortmannin or zardaverine. Insulin also triggers early Mg2+ release from intracellular stores. Additionally, p38 MAPK independently activates SLC41A1-mediated Mg2+ efflux, as its inhibitor (SB202190) reduces efflux ~49% in the absence of insulin.","method":"Fluorescent Mg2+ efflux assay (mag-fura-2) in SLC41A1-overexpressing HEK293 cells with pharmacological inhibitors of ISP and p38 MAPK; adenylate cyclase activator (forskolin) co-treatment","journal":"The Journal of nutrition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological interventions targeting distinct kinases applied to direct Mg2+ efflux assay; single lab","pmids":["26355001"],"is_preprint":false},{"year":2017,"finding":"SLC41A1 knockdown in mesenchymal stromal cells during osteogenesis accelerates mineralization, attenuates high-Mg2+-induced mineralization inhibition, reduces Dkk1 expression, promotes nuclear translocation of phosphorylated β-catenin, and elevates secreted MGP, placing SLC41A1-mediated Mg2+ efflux as a regulator of Wnt/β-catenin signaling during osteogenic differentiation.","method":"siRNA knockdown of Slc41a1 in murine and human MSCs; Alizarin Red mineralization staining; RT-qPCR for osteogenic markers; immunofluorescence for phospho-β-catenin nuclear translocation","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with multiple orthogonal readouts (staining, gene expression, signaling); single lab","pmids":["28222767"],"is_preprint":false},{"year":2017,"finding":"Overexpression of SLC41A1 in HEK293, SH-SY5Y, and HeLa cells significantly reduces phosphorylation of Akt/PKB (Thr308 and/or Ser473) and Erk1/2 (Thr202/Tyr204), attenuating pro-survival signaling. This correlates with decreased intracellular Mg2+ caused by enhanced SLC41A1-mediated Mg2+ efflux.","method":"Dynamic mass redistribution assay; PathScan RTK signaling antibody array; confirmatory Western blot for phospho-Akt and phospho-Erk1/2; mag-fura-2 intracellular Mg2+ measurement in multiple cell lines","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (DMR, antibody array, confirmatory WB, Mg2+ measurement) replicated across three cell lines; single lab","pmids":["29435164"],"is_preprint":false},{"year":2018,"finding":"In polarized MDCK cells, SLC41A1 localizes to the basolateral membrane. A pore mutation (p.Asp262Ala) abolishes SLC41A1-mediated Mg2+ extrusion in HEK293 cells and fails to rescue Mg2+ wasting in slc41a1-morphant zebrafish, while WT mouse SLC41A1 rescues the zebrafish phenotype. 25Mg2+ transport assays indicate SLC41A1 mediates Mg2+ extrusion independently of Na+.","method":"25Mg2+ isotope transport assay in HEK293 cells; pore-dead mutant (p.Asp262Ala) rescue experiment in zebrafish morphants; immunofluorescence localization in MDCK cells","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — isotope-based transport assay, structure-function mutagenesis of ion-conducting pore, in vivo rescue in zebrafish, and subcellular localization across multiple complementary methods","pmids":["30417250"],"is_preprint":false},{"year":2022,"finding":"SLC41A1 knockout mice display normal serum and urine Mg2+ levels under normal and low-Mg2+ dietary conditions, and Mg2+ transporter gene expression (Trpm6, Trpm7, Cnnm2, Slc41a3) is unchanged by genotype. Double knockout of SLC41A1 and SLC41A3 shows the same serum Mg2+ phenotype as SLC41A3 single knockout, demonstrating that SLC41A1 does not compensate for SLC41A3 loss and is not required for systemic Mg2+ homeostasis in mice.","method":"SLC41A1 knockout and SLC41A1/SLC41A3 double-knockout mouse models; serum and urine Mg2+ measurements; dietary Mg2+ restriction challenge; RT-qPCR for Mg2+ transporter genes","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic mouse model with dietary challenge and double KO genetic epistasis; rigorous negative result in vivo","pmids":["36049064"],"is_preprint":false},{"year":2025,"finding":"LPS activates STAT5A, which binds to the SLC41A1 promoter and upregulates SLC41A1 expression, driving Mg2+ efflux from dental pulp stem cells (DPSCs). This Mg2+ depletion destabilizes the mitochondrial permeability transition pore (mPTP) via OSCP–CypD interaction, releasing ROS and mtDNA, activating the AIM2 inflammasome, and inducing GSDMD-mediated pyroptosis. Exogenous Mg2+ supplementation rescues DPSC viability.","method":"STAT5A ChIP/promoter binding assay; SLC41A1 siRNA knockdown; intracellular Mg2+ measurement; mPTP opening assay; mtDNA/ROS quantification; AIM2/GSDMD inflammasome readouts; rescue with exogenous Mg2+","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic experiments (promoter binding, KD, pathway readouts) from single lab; detailed pathway placement but not yet independently replicated","pmids":["40831212"],"is_preprint":false}],"current_model":"SLC41A1 is a plasma membrane-localized Mg2+ transporter (Na+/Mg2+ exchanger) that constitutes the predominant cellular Mg2+ efflux system: it mediates Na+-dependent (and under some conditions Na+-independent) Mg2+ extrusion, is regulated at the plasma membrane by PKA phosphorylation, insulin/ISP signaling, and p38 MAPK, and is controlled post-transcriptionally through N-terminal cytoplasmic domain-dependent endosomal recycling in response to extracellular Mg2+; disease-associated variants (p.A350V gain-of-function; p.R244H and exon-6-deletion loss-of-function) directly alter its transport activity, and its efflux activity is mechanistically upstream of Ca2+-NFATc4 fibrogenic signaling and Wnt/β-catenin osteogenic signaling, while in vivo knockout mouse studies reveal it is dispensable for systemic Mg2+ homeostasis."},"narrative":{"mechanistic_narrative":"SLC41A1 is the predominant cellular Mg2+ efflux carrier, a plasma membrane transporter that extrudes intracellular Mg2+ and thereby sets cytosolic Mg2+ levels that gate multiple downstream signaling cascades [PMID:18367447, PMID:22031603]. It was first established as a bona fide Mg2+ carrier by functional complementation of a Salmonella strain lacking all endogenous Mg2+ transport systems and by direct Mg2+ efflux measurements in HEK293 cells [PMID:18367447]; in oocytes the transporter mediates saturable, voltage-dependent divalent cation uptake with broad ion selectivity (Mg2+, Sr2+, Zn2+, Fe2+, Co2+ and others) [PMID:15713785]. The protein adopts a MgtE-like topology with intracellular N- and C-termini and a ~10-transmembrane-helix architecture, and an intact ion-conducting pore is required for transport, since pore mutations (p.Asp262Ala) abolish Mg2+ extrusion [PMID:21696366, PMID:24491491, PMID:30417250]. SLC41A1 functions as a Na+/Mg2+ exchanger driving Na+-dependent efflux that is blocked by imipramine and quinidine, though Na+-independent extrusion is also observed under isotopic transport conditions [PMID:22031603, PMID:30417250]. Its activity is dynamically regulated: PKA phosphorylation, insulin/ISP signaling, and p38 MAPK modulate efflux capacity, and extracellular Mg2+ controls surface expression through an N-terminal cytoplasmic domain-dependent endosomal recycling and lysosomal degradation pathway [PMID:22031603, PMID:21696366, PMID:26355001]. Endogenous SLC41A1 localizes to renal tubules at the corticomedullary boundary and to the basolateral membrane of polarized epithelial cells [PMID:23661805, PMID:30417250]. By controlling cytosolic Mg2+, SLC41A1 acts upstream of Ca2+-NFATc4 fibrogenic signaling in cardiac fibroblasts [PMID:25263961], Wnt/β-catenin signaling during osteogenic differentiation [PMID:28222767], Akt/Erk pro-survival signaling [PMID:29435164], and an LPS/STAT5A-driven mitochondrial-permeability-transition/AIM2-inflammasome pyroptosis axis [PMID:40831212]. A homozygous exon-6 skipping mutation deleting a transmembrane helix abolishes transport and is associated with renal disease, with zebrafish slc41a1 knockdown producing nephronophthisis-like cystic kidney phenotypes [PMID:23661805]; Parkinson-disease-associated variants directly alter activity (p.A350V gain-of-function with disrupted PKA regulation; p.R244H loss-of-function) [PMID:23976986, PMID:24661466]. Despite these roles, SLC41A1 knockout mice maintain normal serum and urine Mg2+ under normal and low-Mg2+ diets and do not compensate for SLC41A3 loss, indicating it is dispensable for systemic Mg2+ homeostasis in mice [PMID:36049064].","teleology":[{"year":2005,"claim":"Establishing whether SLC41A1 is itself a Mg2+ transporter: heterologous expression revealed it mediates divalent-cation flux, providing the first direct functional identity.","evidence":"Two-electrode voltage-clamp of cloned mouse SLC41A1 in Xenopus oocytes with ionic substitution and saturation kinetics","pmids":["15713785"],"confidence":"High","gaps":["Uptake direction in oocytes appeared Na+/Cl- independent, leaving the physiological transport mode (uptake vs efflux) unresolved","Broad divalent selectivity raised question of in vivo substrate specificity"]},{"year":2008,"claim":"Confirming SLC41A1 as a genuine Mg2+ carrier and defining its cellular action: it localizes to the plasma membrane and mediates Mg2+ efflux, reconciling earlier ambiguity about transport direction.","evidence":"Genetic complementation in Mg2+-transport-deficient Salmonella, whole-cell patch clamp, mag-fura-2 Mg2+ assay, and fractionation in HEK293","pmids":["18367447"],"confidence":"High","gaps":["Coupling ion and exchange stoichiometry not yet defined","Nature of high-molecular-mass complexes not characterized"]},{"year":2011,"claim":"Defining the transport mechanism and its regulation: SLC41A1 was identified as a Na+/Mg2+ exchanger whose activity is controlled by PKA phosphorylation and post-transcriptionally by extracellular Mg2+ via N-terminal-dependent endosomal recycling.","evidence":"Mag-fura-2 efflux with Na+ substitution and exchanger inhibitors; structure-function truncation mutants, surface-expression assays, and TRPM7-deficient cell complementation","pmids":["22031603","21696366"],"confidence":"High","gaps":["PKA phosphorylation site(s) not mapped","Endosomal recycling machinery and adaptor proteins unidentified"]},{"year":2013,"claim":"Linking SLC41A1 transport to disease and tissue context: a loss-of-function exon-6 deletion abolishes transport and a gain-of-function PD variant enhances efflux while uncoupling PKA regulation, connecting transport activity to renal and neurological phenotypes.","evidence":"WT vs mutant transport assays in HEK293, human kidney immunolocalization, zebrafish morpholino knockdown, and split-ubiquitin topology mapping","pmids":["23661805","23976986","24491491"],"confidence":"High","gaps":["Mechanistic basis for A350V PKA insensitivity unresolved","Zebrafish cystic-kidney phenotype not mechanistically tied to Mg2+ transport at the time"]},{"year":2014,"claim":"Placing SLC41A1 within physiological signaling: its Mg2+ efflux sits upstream of Ca2+-NFATc4 fibrogenic signaling, and a R244H PD variant is loss-of-function despite normal membrane targeting.","evidence":"siRNA knockdown in cardiac fibroblasts with Mg2+/Ca2+ measurements and fibrosis-marker readouts; variant transport and WGA co-localization in HEK293","pmids":["25263961","24661466"],"confidence":"Medium","gaps":["Molecular link between Mg2+ efflux and Ca2+ rise not defined","R244H loss-of-function mechanism (folding vs pore) not established"]},{"year":2015,"claim":"Mapping hormonal and kinase control of efflux: insulin/ISP signaling inhibits while p38 MAPK activates SLC41A1, refining the regulatory network beyond PKA.","evidence":"Mag-fura-2 efflux assays in HEK293 with ISP and p38 MAPK pharmacological inhibitors and forskolin","pmids":["26355001"],"confidence":"Medium","gaps":["Direct phosphorylation by p38 vs indirect effect not distinguished","Physiological relevance of insulin regulation in native tissue untested"]},{"year":2017,"claim":"Extending the signaling reach of Mg2+ efflux: SLC41A1 modulates Wnt/β-catenin osteogenic signaling and dampens Akt/Erk pro-survival signaling, establishing it as a broad signaling node.","evidence":"siRNA knockdown in MSCs with mineralization and signaling readouts; overexpression with DMR, antibody arrays and phospho-Western across three cell lines","pmids":["28222767","29435164"],"confidence":"Medium","gaps":["Whether signaling effects are solely Mg2+-dependent vs transport-independent not fully separated","In vivo relevance of osteogenic and survival roles untested"]},{"year":2018,"claim":"Resolving the pore and polarity: a pore-dead mutant fails to transport and fails to rescue zebrafish Mg2+ wasting, confirming transport requires an intact pore and that SLC41A1 acts at the basolateral membrane, with isotopic data showing Na+-independent extrusion.","evidence":"25Mg2+ isotope transport in HEK293, pore mutant (p.Asp262Ala) rescue in zebrafish morphants, MDCK localization","pmids":["30417250"],"confidence":"High","gaps":["Apparent contradiction between Na+-dependent and Na+-independent efflux modes unresolved","Structural model of the conducting pore not determined"]},{"year":2022,"claim":"Testing systemic necessity in vivo: knockout mice retain normal Mg2+ balance and do not compensate for SLC41A3 loss, showing SLC41A1 is dispensable for whole-body Mg2+ homeostasis despite robust in vitro transport.","evidence":"Single and SLC41A1/SLC41A3 double-knockout mice with dietary Mg2+ challenge and transporter expression profiling","pmids":["36049064"],"confidence":"High","gaps":["Tissue-specific or stress-condition roles not excluded","Reconciliation with human disease variants not addressed"]},{"year":2025,"claim":"Connecting transcriptional control to a cell-death program: LPS-driven STAT5A upregulates SLC41A1, and the resulting Mg2+ depletion triggers mitochondrial-permeability-transition-driven AIM2 inflammasome activation and pyroptosis.","evidence":"STAT5A ChIP/promoter binding, SLC41A1 siRNA, mPTP and mtDNA/ROS assays, AIM2/GSDMD readouts and Mg2+ rescue in dental pulp stem cells","pmids":["40831212"],"confidence":"Medium","gaps":["Not independently replicated","Generalizability beyond dental pulp stem cells unknown"]},{"year":null,"claim":"It remains unresolved how SLC41A1 can be a robust Mg2+ efflux carrier and signaling node in vitro yet dispensable for systemic Mg2+ homeostasis in mice, and which physiological or pathological contexts require its activity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the transporter pore","Definitive coupling ion and stoichiometry under physiological conditions unresolved","Tissue context in which SLC41A1 is non-redundant unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,13]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,2,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,9,13]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,2,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,12]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVJ1","full_name":"Solute carrier family 41 member 1","aliases":[],"length_aa":513,"mass_kda":54.9,"function":"Na(+)/Mg(2+) ion exchanger that acts as a predominant Mg(2+) efflux system at the plasma membrane (PubMed:18367447, PubMed:22031603, PubMed:23661805, PubMed:23976986). Transporter activity is driven by the inwardly directed electrochemical gradient for Na(+) ions, thus directly depends on the extracellular Na(+) ion concentration set by Na(+)/K(+) pump (PubMed:22031603, PubMed:23661805). Generates circadian cellular Mg(2+) fluxes that feed back to regulate clock-controlled gene expression and metabolism and facilitate higher energetic demands during the day (PubMed:27074515). Has a role in regulating the activity of ATP-dependent enzymes, including those operating in Krebs cycle and the electron transport chain (By similarity)","subcellular_location":"Cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IVJ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC41A1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC41A1","total_profiled":1310},"omim":[{"mim_id":"619468","title":"NEPHRONOPHTHISIS-LIKE NEPHROPATHY 2; NPHPL2","url":"https://www.omim.org/entry/619468"},{"mim_id":"613164","title":"PARKINSON DISEASE 16; PARK16","url":"https://www.omim.org/entry/613164"},{"mim_id":"610803","title":"SOLUTE CARRIER FAMILY 41, MEMBER 3; SLC41A3","url":"https://www.omim.org/entry/610803"},{"mim_id":"610802","title":"SOLUTE CARRIER FAMILY 41, MEMBER 2; SLC41A2","url":"https://www.omim.org/entry/610802"},{"mim_id":"610801","title":"SOLUTE CARRIER FAMILY 41 (MAGNESIUM TRANSPORTER), MEMBER 1; SLC41A1","url":"https://www.omim.org/entry/610801"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":93.1},{"tissue":"pancreas","ntpm":58.1},{"tissue":"tongue","ntpm":71.0}],"url":"https://www.proteinatlas.org/search/SLC41A1"},"hgnc":{"alias_symbol":["MgtE"],"prev_symbol":[]},"alphafold":{"accession":"Q8IVJ1","domains":[{"cath_id":"-","chopping":"107-503","consensus_level":"medium","plddt":87.9932,"start":107,"end":503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVJ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVJ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVJ1-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC41A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC41A1"},"sequence":{"accession":"Q8IVJ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IVJ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IVJ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVJ1"}},"corpus_meta":[{"pmid":"22031603","id":"PMC_22031603","title":"Human gene SLC41A1 encodes for the Na+/Mg²+ exchanger.","date":"2011","source":"American journal of physiology. 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The transcript is upregulated in kidney with Mg2+ deficiency.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes expressing cloned mouse SLC41A1\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro electrophysiology with kinetic characterization, single lab but multiple ionic substitution controls and saturation kinetics\",\n      \"pmids\": [\"15713785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human SLC41A1 overexpressed in HEK293 cells localizes to the plasma membrane, forms high-molecular-mass protein complexes, mediates Mg2+ efflux (reducing free and total intracellular Mg2+), is temperature-sensitive, and is insensitive to cobalt(III) hexaammine. It functionally complements a Salmonella enterica strain lacking all three endogenous Mg2+ transport systems (CorA, MgtA, MgtB), confirming it as a bona fide Mg2+ carrier.\",\n      \"method\": \"Genetic complementation in Mg2+-transport-deficient Salmonella; whole-cell patch clamp in HEK293; intracellular Mg2+ measurements (mag-fura-2 fluorescence); subcellular fractionation/Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (complementation, patch clamp, fluorescent Mg2+ assay, membrane localization) in a single rigorous study\",\n      \"pmids\": [\"18367447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human SLC41A1 overexpressed in HEK293 cells mediates Na+-dependent Mg2+ efflux; a 3–9-fold elevation of intracellular Mg2+ drives 5–9-fold increased efflux strictly dependent on extracellular Na+ (91% abolished by N-methyl-D-glucamine replacement). Known Na+/Mg2+ exchanger inhibitors imipramine and quinidine inhibited efflux by 88–100%. Transport activity is regulated by cAMP-dependent protein kinase A (PKA) phosphorylation.\",\n      \"method\": \"Fluorescent Mg2+ probe (mag-fura-2) in SLC41A1-overexpressing HEK293 cells; ionic substitution; pharmacological inhibition; PKA stimulation\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (ionic substitution, pharmacology, kinase stimulation) in a single focused study establishing Na+/Mg2+ exchanger identity and PKA regulation\",\n      \"pmids\": [\"22031603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLC41A1 Mg2+ transport function is regulated post-transcriptionally by extracellular Mg2+ via an N-terminal cytoplasmic domain-dependent endosomal recycling mechanism. The N-terminal domain is required for Mg2+-dependent regulation of lysosomal degradation and plasma membrane surface expression. SLC41A1 adopts the same plasma membrane topology as bacterial MgtE, and an intact Mg2+-transporting pore is required to complement growth of TRPM7-deficient cells.\",\n      \"method\": \"Structure-function analysis with truncation/domain mutants; complementation of TRPM7-deficient DT40 B-cells; subcellular localization studies; surface expression assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary experiments (complementation, localization, domain mutagenesis, surface expression) in a single study\",\n      \"pmids\": [\"21696366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A homozygous splice-acceptor mutation (c.698G>T) in SLC41A1 causing in-frame skipping of exon 6 (deletion of a transmembrane helix) completely abolishes the protein's Mg2+ transport function. In normal human kidney, endogenous SLC41A1 localizes specifically to renal tubules at the corticomedullary boundary. Morpholino knockdown of slc41a1 in zebrafish produces ventral body curvature, hydrocephalus, and cystic kidneys similar to nephronophthisis (NPHP) gene knockdowns.\",\n      \"method\": \"Transfection of WT vs. exon-6-deleted mutant SLC41A1 with functional transport assay; immunolocalization in human kidney tissue; morpholino knockdown in zebrafish\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutation with direct transport assay, tissue localization, and in vivo zebrafish phenotype all in one study\",\n      \"pmids\": [\"23661805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The PD-associated substitution p.A350V in SLC41A1 is a gain-of-function mutation that enhances Na+-dependent Mg2+ efflux by ~69% compared to wild-type. This enhanced efflux capacity is accompanied by insensitivity of the mutant to cAMP/PKA stimulation, indicating disrupted hormonal regulation, and results in reduced cell proliferation.\",\n      \"method\": \"Fluorescent Mg2+ efflux assay (mag-fura-2) in HEK293 cells expressing WT or p.A350V SLC41A1; PKA stimulation; proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional transport assay with mutant vs. WT comparison and PKA regulation experiment; single lab\",\n      \"pmids\": [\"23976986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC41A1 membrane topology was experimentally determined to have both N- and C-termini oriented intracellularly, consistent with a 10 transmembrane helix model, using split-ubiquitin yeast two-hybrid assays with orientation-specific membrane marker co-expression.\",\n      \"method\": \"Split-ubiquitin functional assay in S. cerevisiae with C- or N-terminally tagged SLC41A1 fused to Cub-LexA-VP16 reporter, co-expressed with NubI-tagged orientation markers\",\n      \"journal\": \"Magnesium research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct topology assay in yeast, single lab, single method\",\n      \"pmids\": [\"24491491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Using split-ubiquitin yeast two-hybrid screening, putative binding partners of SLC41A1 were identified, including 3-beta-hydroxysteroid-Δ8,Δ7-isomerase, BAP31 (BCAP31), IER3IP1, PPIB, and others mostly localized to the ER, suggesting they contribute to SLC41A1 maturation, folding, and anterograde transport. Co-purification with strep-tagged SLC41A1 identified ACCA1, UBB, ATX2L, HSP7C, and TBB as co-purifying proteins.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid assay; co-purification with strep-tagged SLC41A1 followed by mass spectrometry\",\n      \"journal\": \"Magnesium research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Y2H screen without confirmatory Co-IP validation; no interactor confirmed by mass spectrometry from the Y2H hits; single lab\",\n      \"pmids\": [\"23823179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC41A1 knockdown by siRNA in cardiac fibroblasts attenuates angiotensin II-induced Mg2+ efflux, prevents the associated rise in intracellular Ca2+, reduces NFATc4 nuclear translocation, and suppresses upregulation of fibrosis markers (CTGF, fibronectin, α-SMA), identifying SLC41A1-mediated Mg2+ extrusion as upstream of Ca2+-NFATc4 fibrogenic signaling.\",\n      \"method\": \"siRNA knockdown of SLC41A1 in cardiac fibroblasts; intracellular Mg2+ and Ca2+ measurements; Western blot for fibrosis markers; NFATc4 nuclear translocation assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with multiple downstream readouts placing SLC41A1 in a signaling pathway; single lab\",\n      \"pmids\": [\"25263961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The R244H variant of SLC41A1, identified in an early-onset PD patient, produces a loss-of-function in Mg2+ efflux when expressed in HEK293 cells, while the protein still co-localizes to plasma membrane regions (wheat germ agglutinin-positive areas) similar to wild-type.\",\n      \"method\": \"Stable expression of WT vs. R244H SLC41A1 in HEK293 cells; mag-fluo-4 fluorescent Mg2+ efflux assay; immunofluorescence co-localization with WGA\",\n      \"journal\": \"Parkinsonism & related disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay of variant vs. WT with localization confirmation; single lab, single method per endpoint\",\n      \"pmids\": [\"24661466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin inhibits SLC41A1-mediated Mg2+ efflux by up to ~51% via the insulin-signaling pathway (ISP); this inhibition is reversed by ISP inhibitors wortmannin or zardaverine. Insulin also triggers early Mg2+ release from intracellular stores. Additionally, p38 MAPK independently activates SLC41A1-mediated Mg2+ efflux, as its inhibitor (SB202190) reduces efflux ~49% in the absence of insulin.\",\n      \"method\": \"Fluorescent Mg2+ efflux assay (mag-fura-2) in SLC41A1-overexpressing HEK293 cells with pharmacological inhibitors of ISP and p38 MAPK; adenylate cyclase activator (forskolin) co-treatment\",\n      \"journal\": \"The Journal of nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological interventions targeting distinct kinases applied to direct Mg2+ efflux assay; single lab\",\n      \"pmids\": [\"26355001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLC41A1 knockdown in mesenchymal stromal cells during osteogenesis accelerates mineralization, attenuates high-Mg2+-induced mineralization inhibition, reduces Dkk1 expression, promotes nuclear translocation of phosphorylated β-catenin, and elevates secreted MGP, placing SLC41A1-mediated Mg2+ efflux as a regulator of Wnt/β-catenin signaling during osteogenic differentiation.\",\n      \"method\": \"siRNA knockdown of Slc41a1 in murine and human MSCs; Alizarin Red mineralization staining; RT-qPCR for osteogenic markers; immunofluorescence for phospho-β-catenin nuclear translocation\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with multiple orthogonal readouts (staining, gene expression, signaling); single lab\",\n      \"pmids\": [\"28222767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of SLC41A1 in HEK293, SH-SY5Y, and HeLa cells significantly reduces phosphorylation of Akt/PKB (Thr308 and/or Ser473) and Erk1/2 (Thr202/Tyr204), attenuating pro-survival signaling. This correlates with decreased intracellular Mg2+ caused by enhanced SLC41A1-mediated Mg2+ efflux.\",\n      \"method\": \"Dynamic mass redistribution assay; PathScan RTK signaling antibody array; confirmatory Western blot for phospho-Akt and phospho-Erk1/2; mag-fura-2 intracellular Mg2+ measurement in multiple cell lines\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (DMR, antibody array, confirmatory WB, Mg2+ measurement) replicated across three cell lines; single lab\",\n      \"pmids\": [\"29435164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In polarized MDCK cells, SLC41A1 localizes to the basolateral membrane. A pore mutation (p.Asp262Ala) abolishes SLC41A1-mediated Mg2+ extrusion in HEK293 cells and fails to rescue Mg2+ wasting in slc41a1-morphant zebrafish, while WT mouse SLC41A1 rescues the zebrafish phenotype. 25Mg2+ transport assays indicate SLC41A1 mediates Mg2+ extrusion independently of Na+.\",\n      \"method\": \"25Mg2+ isotope transport assay in HEK293 cells; pore-dead mutant (p.Asp262Ala) rescue experiment in zebrafish morphants; immunofluorescence localization in MDCK cells\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — isotope-based transport assay, structure-function mutagenesis of ion-conducting pore, in vivo rescue in zebrafish, and subcellular localization across multiple complementary methods\",\n      \"pmids\": [\"30417250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLC41A1 knockout mice display normal serum and urine Mg2+ levels under normal and low-Mg2+ dietary conditions, and Mg2+ transporter gene expression (Trpm6, Trpm7, Cnnm2, Slc41a3) is unchanged by genotype. Double knockout of SLC41A1 and SLC41A3 shows the same serum Mg2+ phenotype as SLC41A3 single knockout, demonstrating that SLC41A1 does not compensate for SLC41A3 loss and is not required for systemic Mg2+ homeostasis in mice.\",\n      \"method\": \"SLC41A1 knockout and SLC41A1/SLC41A3 double-knockout mouse models; serum and urine Mg2+ measurements; dietary Mg2+ restriction challenge; RT-qPCR for Mg2+ transporter genes\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic mouse model with dietary challenge and double KO genetic epistasis; rigorous negative result in vivo\",\n      \"pmids\": [\"36049064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LPS activates STAT5A, which binds to the SLC41A1 promoter and upregulates SLC41A1 expression, driving Mg2+ efflux from dental pulp stem cells (DPSCs). This Mg2+ depletion destabilizes the mitochondrial permeability transition pore (mPTP) via OSCP–CypD interaction, releasing ROS and mtDNA, activating the AIM2 inflammasome, and inducing GSDMD-mediated pyroptosis. Exogenous Mg2+ supplementation rescues DPSC viability.\",\n      \"method\": \"STAT5A ChIP/promoter binding assay; SLC41A1 siRNA knockdown; intracellular Mg2+ measurement; mPTP opening assay; mtDNA/ROS quantification; AIM2/GSDMD inflammasome readouts; rescue with exogenous Mg2+\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic experiments (promoter binding, KD, pathway readouts) from single lab; detailed pathway placement but not yet independently replicated\",\n      \"pmids\": [\"40831212\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC41A1 is a plasma membrane-localized Mg2+ transporter (Na+/Mg2+ exchanger) that constitutes the predominant cellular Mg2+ efflux system: it mediates Na+-dependent (and under some conditions Na+-independent) Mg2+ extrusion, is regulated at the plasma membrane by PKA phosphorylation, insulin/ISP signaling, and p38 MAPK, and is controlled post-transcriptionally through N-terminal cytoplasmic domain-dependent endosomal recycling in response to extracellular Mg2+; disease-associated variants (p.A350V gain-of-function; p.R244H and exon-6-deletion loss-of-function) directly alter its transport activity, and its efflux activity is mechanistically upstream of Ca2+-NFATc4 fibrogenic signaling and Wnt/β-catenin osteogenic signaling, while in vivo knockout mouse studies reveal it is dispensable for systemic Mg2+ homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC41A1 is the predominant cellular Mg2+ efflux carrier, a plasma membrane transporter that extrudes intracellular Mg2+ and thereby sets cytosolic Mg2+ levels that gate multiple downstream signaling cascades [#1, #2]. It was first established as a bona fide Mg2+ carrier by functional complementation of a Salmonella strain lacking all endogenous Mg2+ transport systems and by direct Mg2+ efflux measurements in HEK293 cells [#1]; in oocytes the transporter mediates saturable, voltage-dependent divalent cation uptake with broad ion selectivity (Mg2+, Sr2+, Zn2+, Fe2+, Co2+ and others) [#0]. The protein adopts a MgtE-like topology with intracellular N- and C-termini and a ~10-transmembrane-helix architecture, and an intact ion-conducting pore is required for transport, since pore mutations (p.Asp262Ala) abolish Mg2+ extrusion [#3, #6, #13]. SLC41A1 functions as a Na+/Mg2+ exchanger driving Na+-dependent efflux that is blocked by imipramine and quinidine, though Na+-independent extrusion is also observed under isotopic transport conditions [#2, #13]. Its activity is dynamically regulated: PKA phosphorylation, insulin/ISP signaling, and p38 MAPK modulate efflux capacity, and extracellular Mg2+ controls surface expression through an N-terminal cytoplasmic domain-dependent endosomal recycling and lysosomal degradation pathway [#2, #3, #10]. Endogenous SLC41A1 localizes to renal tubules at the corticomedullary boundary and to the basolateral membrane of polarized epithelial cells [#4, #13]. By controlling cytosolic Mg2+, SLC41A1 acts upstream of Ca2+-NFATc4 fibrogenic signaling in cardiac fibroblasts [#8], Wnt/\\u03b2-catenin signaling during osteogenic differentiation [#11], Akt/Erk pro-survival signaling [#12], and an LPS/STAT5A-driven mitochondrial-permeability-transition/AIM2-inflammasome pyroptosis axis [#15]. A homozygous exon-6 skipping mutation deleting a transmembrane helix abolishes transport and is associated with renal disease, with zebrafish slc41a1 knockdown producing nephronophthisis-like cystic kidney phenotypes [#4]; Parkinson-disease-associated variants directly alter activity (p.A350V gain-of-function with disrupted PKA regulation; p.R244H loss-of-function) [#5, #9]. Despite these roles, SLC41A1 knockout mice maintain normal serum and urine Mg2+ under normal and low-Mg2+ diets and do not compensate for SLC41A3 loss, indicating it is dispensable for systemic Mg2+ homeostasis in mice [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing whether SLC41A1 is itself a Mg2+ transporter: heterologous expression revealed it mediates divalent-cation flux, providing the first direct functional identity.\",\n      \"evidence\": \"Two-electrode voltage-clamp of cloned mouse SLC41A1 in Xenopus oocytes with ionic substitution and saturation kinetics\",\n      \"pmids\": [\"15713785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Uptake direction in oocytes appeared Na+/Cl- independent, leaving the physiological transport mode (uptake vs efflux) unresolved\", \"Broad divalent selectivity raised question of in vivo substrate specificity\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirming SLC41A1 as a genuine Mg2+ carrier and defining its cellular action: it localizes to the plasma membrane and mediates Mg2+ efflux, reconciling earlier ambiguity about transport direction.\",\n      \"evidence\": \"Genetic complementation in Mg2+-transport-deficient Salmonella, whole-cell patch clamp, mag-fura-2 Mg2+ assay, and fractionation in HEK293\",\n      \"pmids\": [\"18367447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling ion and exchange stoichiometry not yet defined\", \"Nature of high-molecular-mass complexes not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the transport mechanism and its regulation: SLC41A1 was identified as a Na+/Mg2+ exchanger whose activity is controlled by PKA phosphorylation and post-transcriptionally by extracellular Mg2+ via N-terminal-dependent endosomal recycling.\",\n      \"evidence\": \"Mag-fura-2 efflux with Na+ substitution and exchanger inhibitors; structure-function truncation mutants, surface-expression assays, and TRPM7-deficient cell complementation\",\n      \"pmids\": [\"22031603\", \"21696366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKA phosphorylation site(s) not mapped\", \"Endosomal recycling machinery and adaptor proteins unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking SLC41A1 transport to disease and tissue context: a loss-of-function exon-6 deletion abolishes transport and a gain-of-function PD variant enhances efflux while uncoupling PKA regulation, connecting transport activity to renal and neurological phenotypes.\",\n      \"evidence\": \"WT vs mutant transport assays in HEK293, human kidney immunolocalization, zebrafish morpholino knockdown, and split-ubiquitin topology mapping\",\n      \"pmids\": [\"23661805\", \"23976986\", \"24491491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for A350V PKA insensitivity unresolved\", \"Zebrafish cystic-kidney phenotype not mechanistically tied to Mg2+ transport at the time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placing SLC41A1 within physiological signaling: its Mg2+ efflux sits upstream of Ca2+-NFATc4 fibrogenic signaling, and a R244H PD variant is loss-of-function despite normal membrane targeting.\",\n      \"evidence\": \"siRNA knockdown in cardiac fibroblasts with Mg2+/Ca2+ measurements and fibrosis-marker readouts; variant transport and WGA co-localization in HEK293\",\n      \"pmids\": [\"25263961\", \"24661466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between Mg2+ efflux and Ca2+ rise not defined\", \"R244H loss-of-function mechanism (folding vs pore) not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping hormonal and kinase control of efflux: insulin/ISP signaling inhibits while p38 MAPK activates SLC41A1, refining the regulatory network beyond PKA.\",\n      \"evidence\": \"Mag-fura-2 efflux assays in HEK293 with ISP and p38 MAPK pharmacological inhibitors and forskolin\",\n      \"pmids\": [\"26355001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation by p38 vs indirect effect not distinguished\", \"Physiological relevance of insulin regulation in native tissue untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extending the signaling reach of Mg2+ efflux: SLC41A1 modulates Wnt/\\u03b2-catenin osteogenic signaling and dampens Akt/Erk pro-survival signaling, establishing it as a broad signaling node.\",\n      \"evidence\": \"siRNA knockdown in MSCs with mineralization and signaling readouts; overexpression with DMR, antibody arrays and phospho-Western across three cell lines\",\n      \"pmids\": [\"28222767\", \"29435164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether signaling effects are solely Mg2+-dependent vs transport-independent not fully separated\", \"In vivo relevance of osteogenic and survival roles untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolving the pore and polarity: a pore-dead mutant fails to transport and fails to rescue zebrafish Mg2+ wasting, confirming transport requires an intact pore and that SLC41A1 acts at the basolateral membrane, with isotopic data showing Na+-independent extrusion.\",\n      \"evidence\": \"25Mg2+ isotope transport in HEK293, pore mutant (p.Asp262Ala) rescue in zebrafish morphants, MDCK localization\",\n      \"pmids\": [\"30417250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent contradiction between Na+-dependent and Na+-independent efflux modes unresolved\", \"Structural model of the conducting pore not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Testing systemic necessity in vivo: knockout mice retain normal Mg2+ balance and do not compensate for SLC41A3 loss, showing SLC41A1 is dispensable for whole-body Mg2+ homeostasis despite robust in vitro transport.\",\n      \"evidence\": \"Single and SLC41A1/SLC41A3 double-knockout mice with dietary Mg2+ challenge and transporter expression profiling\",\n      \"pmids\": [\"36049064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific or stress-condition roles not excluded\", \"Reconciliation with human disease variants not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connecting transcriptional control to a cell-death program: LPS-driven STAT5A upregulates SLC41A1, and the resulting Mg2+ depletion triggers mitochondrial-permeability-transition-driven AIM2 inflammasome activation and pyroptosis.\",\n      \"evidence\": \"STAT5A ChIP/promoter binding, SLC41A1 siRNA, mPTP and mtDNA/ROS assays, AIM2/GSDMD readouts and Mg2+ rescue in dental pulp stem cells\",\n      \"pmids\": [\"40831212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"Generalizability beyond dental pulp stem cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SLC41A1 can be a robust Mg2+ efflux carrier and signaling node in vitro yet dispensable for systemic Mg2+ homeostasis in mice, and which physiological or pathological contexts require its activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the transporter pore\", \"Definitive coupling ion and stoichiometry under physiological conditions unresolved\", \"Tissue context in which SLC41A1 is non-redundant unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 13]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 2, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}