Skip to main content

Advertisement

SpringerLink
Log in

Proton-Coupled Oligopeptide Transport (Slc15) in the Brain: Past and Future Research

  • Review Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1 (Slc15A4) in the brain. That family transports endogenous di- and tripeptides and peptidomimetics but also a number of drugs. The review focuses on the pioneering work of David E. Smith in the field in identifying the impact of PepT2 at the choroid plexus (the blood-CSF barrier) as well as PepT2 and PhT1 in brain parenchymal cells. It also discusses recent findings and future directions in relation to brain POTs including cellular and subcellular localization, regulatory pathways, transporter structure, species differences and disease states.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Smith DE, Clemencon B, Hediger MA. Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Asp Med. 2013;34(2-3):323–36.

    CAS  Google Scholar 

  2. Sreedharan S, Stephansson O, Schiöth HB, Fredriksson R. Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters. Gene. 2011;478(1-2):11–8.

    CAS  PubMed  Google Scholar 

  3. Verri T, Barca A, Pisani P, Piccinni B, Storelli C, Romano A. Di- and tripeptide transport in vertebrates: the contribution of teleost fish models. J Comp Physiol B. 2017;187(3):395–462.

    CAS  PubMed  Google Scholar 

  4. Fei YJ, Kanai Y, Nussberger S, Ganapathy V, Leibach FH, Romero MF, Singh SK, Boron WF, Hediger MA. Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature. 1994;368(6471):563–6.

    CAS  PubMed  Google Scholar 

  5. Liu W, Liang R, Ramamoorthy S, Fei YJ, Ganapathy ME, Hediger MA, Ganapathy V, Leibach FH. Molecular cloning of PEPT 2, a new member of the H+/peptide cotransporter family, from human kidney. Biochim Biophys Acta. 1995;1235(2):461–6.

    PubMed  Google Scholar 

  6. Wang H, Fei YJ, Ganapathy V, Leibach FH. Electrophysiological characteristics of the proton-coupled peptide transporter PEPT2 cloned from rat brain. Am J Physiol. 1998;275(4):C967–75.

    CAS  PubMed  Google Scholar 

  7. Yamashita T, Shimada S, Guo W, Sato K, Kohmura E, Hayakawa T, Takagi T, Tohyama M. Cloning and functional expression of a brain peptide/histidine transporter. J Biol Chem. 1997;272(15):10205–11.

    CAS  PubMed  Google Scholar 

  8. Hu Y, Xie Y, Keep RF, Smith DE. Divergent developmental expression and function of the proton-coupled oligopeptide transporters PepT2 and PhT1 in regional brain slices of mouse and rat. J Neurochem. 2014;129(6):955–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sakata K, Yamashita T, Maeda M, Moriyama Y, Shimada S, Tohyama M. Cloning of a lymphatic peptide/histidine transporter. Biochem J. 2001;356(Pt 1):53–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shen H, Smith DE, Keep RF, Brosius FC 3rd. Immunolocalization of the proton-coupled oligopeptide transporter PEPT2 in developing rat brain. Mol Pharm. 2004;1(4):248–56.

    CAS  PubMed  Google Scholar 

  11. Takeuchi H, Suzuki M, Goto R, Tezuka K, Fuchs H, Ishiguro N, Terasaki T, Braun C, Uchida Y. Regional differences in the absolute abundance of transporters, receptors and tight junction molecules at the blood-arachnoid barrier and blood-spinal cord barrier among cervical, thoracic and lumbar spines in dogs. Pharm Res. 2022;39(7):1393–413.

    CAS  PubMed  Google Scholar 

  12. Uchida Y, Goto R, Takeuchi H, Luczak M, Usui T, Tachikawa M, Terasaki T. Abundant expression of OCT2, MATE1, OAT1, OAT3, PEPT2, BCRP, MDR1, and xCT transporters in blood-arachnoid barrier of pig and polarized localizations at CSF- and blood-facing plasma membranes. Drug Metabolism Disposition. 2020;48(2):135–45.

    CAS  PubMed  Google Scholar 

  13. Vanlandewijck M, He L, Mae MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Lavina B, Gouveia L, Sun Y, Raschperger E, Rasanen M, Zarb Y, Mochizuki N, Keller A, Lendahl U, Betsholtz C. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80.

    CAS  PubMed  Google Scholar 

  14. Kugler AR, Olson SC, Smith DE. Disposition of quinapril and quinaprilat in the isolated perfused rat kidney. J Pharmacokinet Biopharm. 1995;23(3):287–305.

    CAS  PubMed  Google Scholar 

  15. Lepsy CS, Guttendorf RJ, Kugler AR, Smith DE. Effects of organic anion, organic cation, and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney. Antimicrob Agents Chemother. 2003;47(2):689–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodriguez CA, Smith DE. Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys. Antimicrob Agents Chemother. 1991;35(11):2395–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Spector R, Johanson CE. The mammalian choroid plexus. Sci Am. 1989;261(5):68–74.

    CAS  PubMed  Google Scholar 

  18. Ghersi-Egea JF, Strazielle N, Catala M, Silva-Vargas V, Doetsch F, Engelhardt B. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 2018;135(3):337–61.

    CAS  PubMed  Google Scholar 

  19. Novotny A, Xiang J, Stummer W, Teuscher NS, Smith DE, Keep RF. Mechanisms of 5-aminolevulinic acid uptake at the choroid plexus. J Neurochem. 2000;75(1):321–8.

    CAS  PubMed  Google Scholar 

  20. Teuscher NS, Novotny A, Keep RF, Smith DE. Functional evidence for presence of PEPT2 in rat choroid plexus: studies with glycylsarcosine. J Pharm Exp Ther. 2000;294(2):494–9.

    CAS  Google Scholar 

  21. Shu C, Shen H, Teuscher NS, Lorenzi PJ, Keep RF, Smith DE. Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture. J Pharm Exp Ther. 2002;301(3):820–9.

    CAS  Google Scholar 

  22. Hu Y, Ocheltree SM, Xiang J, Keep RF, Smith DE. Glycyl-L-glutamine disposition in rat choroid plexus epithelial cells in primary culture: role of PEPT2. Pharm Res. 2005;22(8):1281–6.

    CAS  PubMed  Google Scholar 

  23. Ocheltree SM, Shen H, Hu Y, Xiang J, Keep RF, Smith DE. Role of PEPT2 in the choroid plexus uptake of glycylsarcosine and 5-aminolevulinic acid: studies in wild-type and null mice. Pharm Res. 2004;21(9):1680–5.

    CAS  PubMed  Google Scholar 

  24. Ocheltree SM, Shen H, Hu Y, Xiang J, Keep RF, Smith DE. Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice. J Pharm Exp Ther. 2004;308(2):462–7.

    CAS  Google Scholar 

  25. Shen H, Keep RF, Hu Y, Smith DE. PEPT2 (Slc15a2)-mediated unidirectional transport of cefadroxil from cerebrospinal fluid into choroid plexus. J Pharm Exp Ther. 2005;315(3):1101–8.

    CAS  Google Scholar 

  26. Shen H, Smith DE, Keep RF, Xiang J, Brosius FC 3rd. Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus. J Biol Chem. 2003;278(7):4786–91.

    CAS  PubMed  Google Scholar 

  27. Teuscher NS, Keep RF, Smith DE. PEPT2-mediated uptake of neuropeptides in rat choroid plexus. Pharm Res. 2001;18(6):807–13.

    CAS  PubMed  Google Scholar 

  28. Teuscher NS, Shen H, Shu C, Xiang J, Keep RF, Smith DE. Carnosine uptake in rat choroid plexus primary cell cultures and choroid plexus whole tissue from PEPT2 null mice. J Neurochem. 2004;89(2):375–82.

    CAS  PubMed  Google Scholar 

  29. Ocheltree SM, Shen H, Hu Y, Keep RF, Smith DE. Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: in vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J Pharm Exp Ther. 2005;315(1):240–7.

    CAS  Google Scholar 

  30. Shen H, Ocheltree SM, Hu Y, Keep RF, Smith DE. Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice. Drug Metab Dispos. 2007;35(7):1209–16.

    PubMed  Google Scholar 

  31. Kamal MA, Jiang H, Hu Y, Keep RF, Smith DE. Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice. Am J Phys Regul Integr Comp Phys. 2009;296(4):R986–91.

    CAS  Google Scholar 

  32. Chen X, Keep RF, Liang Y, Zhu HJ, Hammarlund-Udenaes M, Hu Y, Smith DE. Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: a microdialysis study. Biochem Pharmacol. 2017;131:89–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith DE, Hu Y, Shen H, Nagaraja TN, Fenstermacher JD, Keep RF. Distribution of glycylsarcosine and cefadroxil among cerebrospinal fluid, choroid plexus, and brain parenchyma after intracerebroventricular injection is markedly different between wild-type and Pept2 null mice. J Cereb Blood Flow Metab. 2011;31(1):250–61.

    CAS  PubMed  Google Scholar 

  34. Hu Y, Shen H, Keep RF, Smith DE. Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity. J Neurochem. 2007;103(5):2058–65.

    CAS  PubMed  Google Scholar 

  35. Jiang H, Hu Y, Keep RF, Smith DE. Enhanced antinociceptive response to intracerebroventricular kyotorphin in Pept2 null mice. J Neurochem. 2009;109(5):1536–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xiang J, Chiang PP, Hu Y, Smith DE, Keep RF. Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures. Neurosci Lett. 2006;396(3):225–9.

    CAS  PubMed  Google Scholar 

  37. Xiang J, Hu Y, Smith DE, Keep RF. PEPT2-mediated transport of 5-aminolevulinic acid and carnosine in astrocytes. Brain Res. 2006;1122(1):18–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiang J, Jiang H, Hu Y, Smith DE, Keep RF. Kyotorphin transport and metabolism in rat and mouse neonatal astrocytes. Brain Res. 2010;1347:11–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Fujita T, Kishida T, Wada M, Okada N, Yamamoto A, Leibach FH, Ganapathy V. Functional characterization of brain peptide transporter in rat cerebral cortex: identification of the high-affinity type H+/peptide transporter PEPT2. Brain Res. 2004;997(1):52–61.

    CAS  PubMed  Google Scholar 

  40. Lopachev AV, Abaimov DA, Filimonov IS, Kulichenkova KN, Fedorova TN. An assessment of the transport mechanism and intraneuronal stability of L-carnosine. Amino Acids. 2022;54(8):1115–22.

    CAS  PubMed  Google Scholar 

  41. Berger UV, Hediger MA. Distribution of peptide transporter PEPT2 mRNA in the rat nervous system. Anat Embryol. 1999;199(5):439–49.

    CAS  Google Scholar 

  42. Wang XX, Hu Y, Keep RF, Toyama-Sorimachi N, Smith DE. A novel role for PHT1 in the disposition of l-histidine in brain: in vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. Biochem Pharmacol. 2017;124:94–102.

    CAS  PubMed  Google Scholar 

  43. Smith DE, Johanson CE, Keep RF. Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Deliv Rev. 2004;56(12):1765–91.

    CAS  PubMed  Google Scholar 

  44. Uchida Y, Takeuchi H, Goto R, Braun C, Fuchs H, Ishiguro N, Takao M, Tano M, Terasaki T. A human blood-arachnoid barrier atlas of transporters, receptors, enzymes, and tight junction and marker proteins: comparison with dog and pig in absolute abundance. J Neurochem. 2022;161(2):187–208.

    CAS  PubMed  Google Scholar 

  45. Sasawatari S, Okamura T, Kasumi E, Tanaka-Furuyama K, Yanobu-Takanashi R, Shirasawa S, Kato N, Toyama-Sorimachi N. The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterol. 2011;140(5):1513–25.

    CAS  Google Scholar 

  46. Song F, Yi Y, Li C, Hu Y, Wang J, Smith DE, Jiang H. Regulation and biological role of the peptide/histidine transporter SLC15A3 in toll-like receptor-mediated inflammatory responses in macrophage. Cell Death Dis. 2018;9(7):770.

    PubMed  PubMed Central  Google Scholar 

  47. Sun D, Wang Y, Tan F, Fang D, Hu Y, Smith DE, Jiang H. Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human. Mol Pharm. 2013;10(4):1409–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang Y, Sun D, Song F, Hu Y, Smith DE, Jiang H. Expression and regulation of the proton-coupled oligopeptide transporter PhT2 by LPS in macrophages and mouse spleen. Mol Pharm. 2014;11(6):1880–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hu Y, Song F, Jiang H, Nuñez G, Smith DE. SLC15A2 and SLC15A4 mediate the transport of bacterially derived Di/tripeptides to enhance the nucleotide-binding oligomerization domain-dependent immune response in mouse bone marrow-derived macrophages. J Immunol. 2018;201(2):652–62.

    CAS  PubMed  Google Scholar 

  50. Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL, Aerts J, Berx G, Boeckxstaens GE, Vandenbroucke RE, Vereecke L, Moechars D, Guilliams M, Van Ginderachter JA, Saeys Y, Movahedi K. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci. 2019;22(6):1021–35.

    PubMed  Google Scholar 

  51. Dieck ST, Heuer H, Ehrchen J, Otto C, Bauer K. The peptide transporter PepT2 is expressed in rat brain and mediates the accumulation of the fluorescent dipeptide derivative beta-ala-Lys-Nepsilon-AMCA in astrocytes. GLIA. 1999;25(1):10–20.

    CAS  PubMed  Google Scholar 

  52. Wada M, Miyakawa S, Shimada A, Okada N, Yamamoto A, Fujita T. Functional linkage of H+/peptide transporter PEPT2 and Na+/H+ exchanger in primary cultures of astrocytes from mouse cerebral cortex. Brain Res. 2005;1044(1):33–41.

    CAS  PubMed  Google Scholar 

  53. Escartin C, Galea E, Lakatos A, O'Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhauser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3):312–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang C, Chu C, Ji X, Luo G, Xu C, He H, Yao J, Wu J, Hu J, Jin Y. Biology of peptide transporter 2 in mammals: new insights into its function, structure and regulation. Cells. 2022;11(18):14.

    CAS  Google Scholar 

  55. Noshiro R, Anzai N, Sakata T, Miyazaki H, Terada T, Shin HJ, He X, Miura D, Inui K, Kanai Y, Endou H. The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. Kidney Int. 2006;70(2):275–82.

    CAS  PubMed  Google Scholar 

  56. Zhang Y, Tu H, Hao Y, Li D, Yang Y, Yuan Y, Guo Z, Li L, Wang H, Cai H. Oligopeptide transporter Slc15A modulates macropinocytosis in Dictyostelium by maintaining intracellular nutrient status. J Cell Sci. 2022;135(7):01.

    Google Scholar 

  57. Minhas GS, Newstead S. Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters. Proc Natl Acad Sci U S A. 2019;116(3):804–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ural-Blimke Y, Flayhan A, Strauss J, Rantos V, Bartels K, Nielsen R, Pardon E, Steyaert J, Kosinski J, Quistgaard EM, Low C. Structure of prototypic peptide transporter DtpA from E. coli in complex with Valganciclovir provides insights into drug binding of human PepT1. J Am Chem Soc. 2019;141(6):2404–12.

    CAS  PubMed  Google Scholar 

  59. Minhas GS, Newstead S. Recent advances in understanding prodrug transport through the SLC15 family of proton-coupled transporters. Biochem Soc Trans. 2020;48(2):337–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Parker JL, Deme JC, Wu Z, Kuteyi G, Huo J, Owens RJ, Biggin PC, Lea SM, Newstead S. Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals. Sci Adv. 2021;7(35):08.

    Google Scholar 

  61. Song F, Hu Y, Jiang H, Smith DE. Species differences in human and rodent PEPT2-mediated transport of Glycylsarcosine and Cefadroxil in Pichia Pastoris Transformants. Drug Metab Dispos. 2017;45(2):130–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hu Y, Xie Y, Wang Y, Chen X, Smith DE. Development and characterization of a novel mouse line humanized for the intestinal peptide transporter PEPT1. Mol Pharm. 2014;11(10):3737–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Uchida Y, Zhang Z, Tachikawa M, Terasaki T. Quantitative targeted absolute proteomics of rat blood-cerebrospinal fluid barrier transporters: comparison with a human specimen. J Neurochem. 2015;134(6):1104–15.

    CAS  PubMed  Google Scholar 

  64. Zhang Z, Tachikawa M, Uchida Y, Terasaki T. Drug clearance from cerebrospinal fluid mediated by organic anion transporters 1 (Slc22a6) and 3 (Slc22a8) at arachnoid membrane of rats. Mol Pharm. 2018;15(3):911–22.

    CAS  PubMed  Google Scholar 

  65. Casas A. Clinical uses of 5-aminolaevulinic acid in photodynamic treatment and photodetection of cancer: a review. Cancer Lett. 2020;490:165–73.

    CAS  PubMed  Google Scholar 

  66. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, Group AL-GS. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401.

    CAS  PubMed  Google Scholar 

  67. McNicholas K, MacGregor MN, Gleadle JM. In order for the light to shine so brightly, the darkness must be present-why do cancers fluoresce with 5-aminolaevulinic acid? Br J Cancer. 2019;121(8):631–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Harada Y, Murayama Y, Takamatsu T, Otsuji E, Tanaka H. 5-Aminolevulinic acid-induced Protoporphyrin IX fluorescence imaging for tumor detection: recent advances and challenges. Int J Mol Sci. 2022;23(12):6478.

  69. Doring F, Walter J, Will J, Focking M, Boll M, Amasheh S, Clauss W, Daniel H. Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications. J Clin Investig. 1998;101(12):2761–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hou C, Yamaguchi S, Ishi Y, Terasaka S, Kobayashi H, Motegi H, Hatanaka KC, Houkin K. Identification of PEPT2 as an important candidate molecule in 5-ALA-mediated fluorescence-guided surgery in WHO grade II/III gliomas. J Neuro-Oncol. 2019;143(2):197–206.

    CAS  Google Scholar 

  71. Kamal MA, Keep RF, Smith DE. Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharm. 2008;23(4):236–42.

    CAS  Google Scholar 

  72. Pinsonneault J, Nielsen CU, Sadee W. Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions. J Pharm Exp Ther. 2004;311(3):1088–96.

    CAS  Google Scholar 

  73. Tchernitchko D, Tavernier Q, Lamoril J, Schmitt C, Talbi N, Lyoumi S, Robreau AM, Karim Z, Gouya L, Thervet E, Karras A, Puy H, Pallet N. A variant of peptide transporter 2 predicts the severity of Porphyria-associated kidney disease. J Am Soc Nephrol. 2017;28(6):1924–32.

    CAS  PubMed  Google Scholar 

  74. Pischik E, Baumann K, Karpenko A, Kauppinen R. Pathogenesis of acute encephalopathy in acute hepatic porphyria. J Neurol. 2023;270(5):2613–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sobin C, Flores-Montoya MG, Gutierrez M, Parisi N, Schaub T. delta-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2 2 haplotype (hPEPT2 2) differently influence neurobehavior in low-level lead exposed children. Neurotoxicol Teratol. 2015;47:137–45.

    CAS  PubMed  Google Scholar 

  76. Tossman U, Eriksson S, Delin A, Hagenfeldt L, Law D, Ungerstedt U. Brain amino acids measured by intracerebral dialysis in portacaval shunted rats. J Neurochem. 1983;41(4):1046–51.

    CAS  PubMed  Google Scholar 

  77. Zanchin G, Rigotti P, Dussini N, Vassanelli P, Battistin L. Cerebral amino acid levels and uptake in rats after portocaval anastomosis: II. Regional studies in vivo. J Neurosci Res. 1979;4(4):301–10.

    CAS  PubMed  Google Scholar 

  78. Weiser M, Riederer P, Kleinberger G. Human cerebral free amino acids in hepatic coma. J Neural Transm Suppl. 1978;14:95–102.

    CAS  Google Scholar 

  79. He CF, Liu YS, Cheng YL, Gao JP, Pan TM, Han JW, Quan C, Sun LD, Zheng HF, Zuo XB, Xu SX, Sheng YJ, Yao S, Hu WL, Li Y, Yu ZY, Yin XY, Zhang XJ, Cui Y, Yang S. TNIP1, SLC15A4, ETS1, RasGRP3 and IKZF1 are associated with clinical features of systemic lupus erythematosus in a Chinese Han population. Lupus. 2010;19(10):1181–6.

    PubMed  Google Scholar 

  80. Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta ML, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson AA, Truedsson L, Eriksson C, Rantapää-Dahlqvist S, Sjöwall C, Julkunen H, Criswell LA, Graham RR, Behrens TW, et al. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet. 2013;21(9):994–9.

    CAS  PubMed  Google Scholar 

  81. Zhang M, Chen F, Zhang D, Zhai Z, Hao F. Association study between SLC15A4 polymorphisms and haplotypes and systemic lupus erythematosus in a Han Chinese population. Genet Test Mol Biomarker. 2016;20(8):451–8.

    CAS  Google Scholar 

  82. Zuo XB, Sheng YJ, Hu SJ, Gao JP, Li Y, Tang HY, Tang XF, Cheng H, Yin XY, Wen LL, Sun LD, Yang S, Cui Y, Zhang XJ. Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population. Rheumatol Int. 2014;34(4):459–64.

    CAS  PubMed  Google Scholar 

  83. Rimann I, Gonzalez-Quintial R, Baccala R, Kiosses WB, Teijaro JR, Parker CG, Li X, Beutler B, Kono DH, Theofilopoulos AN. The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes. Proc Natl Acad Sci U S A. 2022;119(14):e2200544119.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Michigan, R5018 BSRB 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA

    Jianming Xiang & Richard F. Keep

Authors
  1. Jianming Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard F. Keep
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RFK performed the initial literature search. JX and RFK wrote and edited the paper.

Corresponding author

Correspondence to Richard F. Keep.

Ethics declarations

Conflict of Interest

None.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiang, J., Keep, R.F. Proton-Coupled Oligopeptide Transport (Slc15) in the Brain: Past and Future Research. Pharm Res 40, 2533–2540 (2023). https://doi.org/10.1007/s11095-023-03550-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03550-9

Keywords

Search

Navigation