| Aspect | Key points | Species/context (rat vs human vs mouse) | Key sources (with year, journal, DOI/URL) |
|---|---|---|---|
| Verified identity | **Rat Slc13a2 corresponds to NaDC1 / Na(+)-dicarboxylate cotransporter 1**, a member of the **SLC13/DASS family**. Gathered evidence consistently treats **SLC13A2/NaDC1/NADC-1/SDCT1** as the renal/intestinal sodium-coupled dicarboxylate transporter relevant to citrate/succinate transport; this matches the UniProt P70545 description for *Rattus norvegicus*. | Rat identity supported by rat-localization/review evidence; human and mouse papers are orthologous context used for mechanism and physiology. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000000, pqac-00000001, pqac-00000015) |
| Protein architecture/family | NaDC1 is described as an **11-transmembrane helix** transporter in the **SLC13/DASS** family, with intracellular N-terminus and extracellular C-terminus and conserved N-glycosylation features. | Architecture summarized mainly from human-focused review, but applied to mammalian NaDC1 orthologs including rat. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385 (pqac-00000000, pqac-00000015) |
| Main substrates | Preferred substrates are **divalent Krebs-cycle/dicarboxylate anions**, especially **succinate** (high affinity), with **citrate** also transported but generally at lower affinity; NaDC1 is broadly discussed as mediating **Na+-dependent cotransport of citrate and succinate**. | Rat review/localization evidence plus human structural and clinical context. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Chi et al., 2024, *Science Advances*, doi:10.1126/sciadv.adl3685, https://doi.org/10.1126/sciadv.adl3685; Shimshilashvili et al., 2020, *Front Pharmacol*, doi:10.3389/fphar.2020.00405, https://doi.org/10.3389/fphar.2020.00405 (pqac-00000000, pqac-00000004, pqac-00000011, pqac-00000015) |
| Coupling/stoichiometry | NaDC1 is an **electrogenic Na+-coupled symporter**. Review evidence states a **3 Na+:1 anion** coupling ratio; one commentary excerpt notes **2 Na+-succinate cotransport** in the context of variant discussion, so stoichiometry in the gathered evidence is not entirely uniform. The strongest explicit stoichiometric statement in the evidence base is **3:1**. | 3:1 ratio from review/general mammalian context; variant commentary not rat-specific. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Romero, 2010, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00432.2010, https://doi.org/10.1152/ajprenal.00432.2010 (pqac-00000000, pqac-00000007, pqac-00000015) |
| Transport mechanism | Recent structural work supports an **elevator-type transport mechanism** with a stable scaffold/dimerization domain and a mobile core domain. Human NaDC1 cryo-EM structures captured **apo, citrate-bound, and inhibitor-bound outward-facing states**; protomers can adopt different conformations, suggesting largely independent transport cycles within the dimer. | Mechanism shown directly for **human SLC13A2/NaDC1**; relevant by homology to rat Slc13a2. | Chi et al., 2024, *Science Advances*, doi:10.1126/sciadv.adl3685, https://doi.org/10.1126/sciadv.adl3685 (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011) |
| Substrate/ion recognition | Human NaDC1 structures place **citrate** in a pocket at the scaffold-core interface with two Na+ sites (**Na1, Na2**). Key residues implicated in transport/substrate recognition include **Ser140, Asn141, Thr142, Thr240, Thr471, Thr474, Asn476, Ala518**, and **Arg108**; mutagenesis reduced citrate-induced currents. | Direct evidence from **human NaDC1** structural/functional study; used here as current mechanistic understanding for the orthologous transporter family. | Chi et al., 2024, *Science Advances*, doi:10.1126/sciadv.adl3685, https://doi.org/10.1126/sciadv.adl3685 (pqac-00000008, pqac-00000009, pqac-00000010) |
| Tissue localization | NaDC1 is **widely expressed in kidney and gastrointestinal epithelium**. In rat, evidence places it in the **outer stripe of the outer medulla** and **luminal membranes of the superficial renal cortex**. Human clinical genetics review also notes expression in **renal proximal tubule and small intestinal cells**. | Rat-specific localization available; human expression used as orthologous corroboration. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Çalışkan et al., 2023, *Journal of Urological Surgery*, doi:10.4274/jus.galenos.2023.2023-10-2, https://doi.org/10.4274/jus.galenos.2023.2023-10-2 (pqac-00000000, pqac-00000013) |
| Subcellular localization | NaDC1 localizes to the **apical/luminal (brush-border) membrane** of **proximal tubule epithelial cells** and is also discussed as apical in intestine/small intestinal villus epithelium. | Rat apical kidney localization supported directly; intestinal/apical context supported by review and human study. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Romero, 2010, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00432.2010, https://doi.org/10.1152/ajprenal.00432.2010; Çalışkan et al., 2023, *Journal of Urological Surgery*, doi:10.4274/jus.galenos.2023.2023-10-2, https://doi.org/10.4274/jus.galenos.2023.2023-10-2 (pqac-00000000, pqac-00000005, pqac-00000007, pqac-00000012, pqac-00000013) |
| Segment-specific renal expression/regulation | In mouse kidney, NaDC1 expression is highest/adaptive in **cortical proximal tubule segments** (**PCT and PST-MR**), with less response in **PST-OM**; this demonstrates axial heterogeneity in regulation. | Mouse regulation study; relevant physiological context for mammalian NaDC1, not direct rat measurement. | Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000002, pqac-00000003) |
| Regulation by acid-base status | Gathered evidence cites that **chronic metabolic acidosis increases NaDC1 mRNA and protein abundance in rat kidney** and that acid loading alters citrate transport and NaDC1 expression/activity in proximal tubule. | Rat cited in review of prior literature; mouse experimental support for acid-loading response. | Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000001, pqac-00000002, pqac-00000003) |
| Regulation by potassium status | **Hypokalemia / K+-free diet** increases NaDC1 expression in cortical proximal tubule segments and decreases urinary citrate excretion; older literature cited in the evidence notes chronic potassium depletion stimulates the renal brush-border Na-citrate cotransporter. | Direct experimental evidence in mouse; rat cited via prior literature in review/discussion. | Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000001, pqac-00000002, pqac-00000003) |
| Key regulator: NBCe1-A | **NBCe1-A** is necessary for normal basal and adaptive renal citrate handling; its deletion reduces NaDC1 expression in cortical proximal tubule, increases urinary citrate excretion, and blunts hypokalemia-induced NaDC1 upregulation. | Demonstrated in **mouse**; mechanistically relevant to renal NaDC1 regulation. | Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000001, pqac-00000002, pqac-00000003) |
| Key interacting protein: SLC26A6 | NaDC1 **functionally and physically interacts with SLC26A6**. Evidence supports bidirectional modulation, with SLC26A6 restricting NaDC1 activity and thereby contributing to coordinated **oxalate/citrate homeostasis** relevant to stone risk. | Mechanistic evidence primarily human/cell systems and review synthesis; kidney relevance broadly mammalian. | Ohana et al., 2013, *JASN*, doi:10.1681/ASN.2013010080, https://doi.org/10.1681/ASN.2013010080; Shimshilashvili et al., 2020, *Front Pharmacol*, doi:10.3389/fphar.2020.00405, https://doi.org/10.3389/fphar.2020.00405; Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385 (pqac-00000000, pqac-00000004, pqac-00000006, pqac-00000015) |
| Additional modulators | Gathered evidence cites regulation of NaDC1 by **protein kinase C**, **NHERF2**, **SGK isoforms**, **protein kinase B**, **cyclophilin B** (biogenesis), and **endothelin B receptor** dependence for acid regulation. **IRBIT** inhibits NaDC1-mediated succinate transport by about 50% in the SLC26A6/NaDC1 context. | Mostly prior literature summarized in mouse/human reviews rather than rat-specific direct assays in the retrieved text. | Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019; Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385 (pqac-00000001, pqac-00000002, pqac-00000015) |
| Physiological role in kidney | NaDC1 is the **primary renal apical citrate reabsorption pathway** discussed in the evidence base, mediating a major portion of filtered citrate reclamation in proximal tubule and thereby influencing systemic acid-base handling because metabolized citrate yields bicarbonate equivalents. | Rat/human/mouse physiology synthesized across studies; one review cites >65% citrate reabsorption after filtration from rabbit data. | Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Osis et al., 2019, *Am J Physiol Renal Physiol*, doi:10.1152/ajprenal.00015.2019, https://doi.org/10.1152/ajprenal.00015.2019 (pqac-00000000, pqac-00000003, pqac-00000015) |
| Disease/clinical link: nephrolithiasis | By lowering urinary citrate when reabsorption is increased, NaDC1 is linked to **hypocitraturia** and thus to risk of **calcium oxalate/calcium-containing kidney stones**, since citrate inhibits Ca2+ stone formation. Increased intrarenal NaDC1 expression has been reported in stone formers with acidic urine, and SLC26A6–NaDC1 dysregulation may further increase lithogenic risk. | Human disease relevance strongest; rat/mouse data mainly mechanistic. | Çalışkan et al., 2023, *Journal of Urological Surgery*, doi:10.4274/jus.galenos.2023.2023-10-2, https://doi.org/10.4274/jus.galenos.2023.2023-10-2; Yang et al., 2021, *Molecular Medicine Reports*, doi:10.3892/mmr.2021.12385, https://doi.org/10.3892/mmr.2021.12385; Chi et al., 2024, *Science Advances*, doi:10.1126/sciadv.adl3685, https://doi.org/10.1126/sciadv.adl3685 (pqac-00000000, pqac-00000011, pqac-00000012, pqac-00000013, pqac-00000015) |
| Recent 2023 genetic study | In a 2023 cohort of **96 calcium stone patients**, urinary citrate differed markedly between normocitraturic and hypocitraturic groups, but **rs11567842 (I550V)** genotype frequencies did **not** differ significantly; this study concluded that this SNP alone did not explain hypocitraturia. | Human clinical genetics; useful for disease relevance but not direct rat annotation. | Çalışkan et al., 2023, *Journal of Urological Surgery*, doi:10.4274/jus.galenos.2023.2023-10-2, https://doi.org/10.4274/jus.galenos.2023.2023-10-2 (pqac-00000012, pqac-00000013) |
| Recent 2024 structural advance | 2024 cryo-EM work is the key recent advance: it resolved **human NaDC1** with **citrate-bound** and **ACA inhibitor-bound** states, identified an **allosteric/peripheral inhibitor site** near the cytosolic membrane, and provided a framework for **future drug design** targeting NaDC1. | Human structural biology; strong mechanistic relevance for rat ortholog inference. | Chi et al., 2024, *Science Advances*, doi:10.1126/sciadv.adl3685, https://doi.org/10.1126/sciadv.adl3685 (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011) |


*Table: This table summarizes the verified identity, transport properties, localization, regulation, and physiological relevance of rat Slc13a2/NaDC1 using only claims supported by the gathered evidence. It also distinguishes rat-specific observations from human and mouse ortholog evidence used to interpret current functional annotation.*