| Structural highlights
Function
S22A1_HUMAN Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930).[UniProtKB:O08966][UniProtKB:Q63089][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] Mediates the uptake of 1-methyl-4-phenylpyridinium (MPP(+)).[22] Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).[23] Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).[24] Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).[25]
Publication Abstract from PubMed
Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.
Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.,Zeng YC, Sobti M, Quinn A, Smith NJ, Brown SHJ, Vandenberg JI, Ryan RM, O'Mara ML, Stewart AG Nat Commun. 2023 Oct 11;14(1):6374. doi: 10.1038/s41467-023-42086-9. PMID:37821493[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hayer M, Bönisch H, Brüss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. PMID:11388889 doi:10.1017/S0003480099007770
- ↑ van Montfoort JE, Müller M, Groothuis GM, Meijer DK, Koepsell H, Meier PJ. Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5 PMID:11408531
- ↑ Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8. PMID:11907186 doi:10.1124/jpet.301.1.293
- ↑ Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, Eichelbaum M, Koepsell H. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002 Nov;12(8):591-5. PMID:12439218 doi:10.1097/00008571-200211000-00002
- ↑ Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, Ferrin TE, Herskowitz I, Giacomini KM. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5902-7. PMID:12719534 doi:10.1073/pnas.0730858100
- ↑ Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E, Hirsch JR. Regulation of the human organic cation transporter hOCT1. J Cell Physiol. 2004 Dec;201(3):420-8. PMID:15389554 doi:10.1002/jcp.20081
- ↑ Lips KS, Volk C, Schmitt BM, Pfeil U, Arndt P, Miska D, Ermert L, Kummer W, Koepsell H. Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol. 2005 Jul;33(1):79-88. PMID:15817714 doi:10.1165/rcmb.2004-0363OC
- ↑ Müller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005 Dec 5;70(12):1851-60. PMID:16263091 doi:10.1016/j.bcp.2005.09.011
- ↑ Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, Inui K. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86. PMID:16272756 doi:10.2133/dmpk.20.379
- ↑ Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52. PMID:16581093 doi:10.1016/j.neuropharm.2006.01.005
- ↑ Taubert D, Grimberg G, Stenzel W, Schömig E. Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons. PLoS One. 2007 Apr 25;2(4):e385. PMID:17460754 doi:10.1371/journal.pone.0000385
- ↑ Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, Sabolić I, Koepsell H, Brockmöller J. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009 Sep;86(3):299-306. PMID:19536068 doi:10.1038/clpt.2009.92
- ↑ Winter TN, Elmquist WF, Fairbanks CA. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm. 2011 Feb 7;8(1):133-42. PMID:21128598 doi:10.1021/mp100180a
- ↑ Han TK, Everett RS, Proctor WR, Ng CM, Costales CL, Brouwer KL, Thakker DR. Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol. 2013 Aug;84(2):182-9. PMID:23680637 doi:10.1124/mol.112.084517
- ↑ Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ, Chien HC, Zhang Y, Morrissey KM, Liu J, Ostrem J, Younger NS, Kurhanewicz J, Shokat KM, Ashrafi K, Giacomini KM. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9983-8. PMID:24961373 doi:10.1073/pnas.1314939111
- ↑ Jensen O, Matthaei J, Klemp HG, Meyer MJ, Brockmöller J, Tzvetkov MV. Isobutyrylcarnitine as a Biomarker of OCT1 Activity and Interspecies Differences in its Membrane Transport. Front Pharmacol. 2021 May 10;12:674559. PMID:34040533 doi:10.3389/fphar.2021.674559
- ↑ Meyer MJ, Schreier PCF, Basaran M, Vlasova S, Seitz T, Brockmöller J, Zdrazil B, Tzvetkov MV. Amino acids in transmembrane helix 1 confer major functional differences between human and mouse orthologs of the polyspecific membrane transporter OCT1. J Biol Chem. 2022 Jun;298(6):101974. PMID:35469921 doi:10.1016/j.jbc.2022.101974
- ↑ Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giacomini KM. Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol. 1997 Jun;51(6):913-21. PMID:9187257 doi:10.1124/mol.51.6.913
- ↑ Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997 Jul;16(7):871-81. PMID:9260930 doi:10.1089/dna.1997.16.871
- ↑ Zhang L, Schaner ME, Giacomini KM. Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther. 1998 Jul;286(1):354-61 PMID:9655880
- ↑ Hau RK, Klein RR, Wright SH, Cherrington NJ. Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier. Drug Metab Dispos. 2022 Jun;50(6):770-780. PMID:35307651 doi:10.1124/dmd.121.000748
- ↑ Hayer M, Bönisch H, Brüss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. PMID:11388889 doi:10.1017/S0003480099007770
- ↑ Hayer M, Bönisch H, Brüss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. PMID:11388889 doi:10.1017/S0003480099007770
- ↑ Hayer M, Bönisch H, Brüss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. PMID:11388889 doi:10.1017/S0003480099007770
- ↑ Hayer M, Bönisch H, Brüss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. PMID:11388889 doi:10.1017/S0003480099007770
- ↑ Zeng YC, Sobti M, Quinn A, Smith NJ, Brown SHJ, Vandenberg JI, Ryan RM, O'Mara ML, Stewart AG. Structural basis of promiscuous substrate transport by Organic Cation Transporter 1. Nat Commun. 2023 Oct 11;14(1):6374. PMID:37821493 doi:10.1038/s41467-023-42086-9
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