Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

被引:7
作者
Bakos, Eva [1 ]
Nemet, Orsolya [1 ]
Kucsma, Nora [1 ]
Tokesi, Natalia [1 ]
Stieger, Bruno [2 ]
Rushing, Elisabeth [2 ]
Tokes, Anna-Maria [3 ]
Kele, Peter [4 ]
Tusnady, Gabor E. [1 ]
Ozvegy-Laczka, Csilla [1 ]
机构
[1] RCNS, Inst Enzymol, Budapest, Hungary
[2] Univ Zurich, Univ Hosp Zurich, Zurich, Switzerland
[3] Semmelweis Univ, Dept Pathol Forens & Insurance Med, Budapest, Hungary
[4] RCNS, Inst Organ Chem, Budapest, Hungary
基金
芬兰科学院; 瑞士国家科学基金会;
关键词
organic anion transporting polypeptide (OATP); isoform; choroid plexus; testis; steroid transport; human brain; MEDIATED TRANSPORT; PANCREATIC-CANCER; MESSENGER-RNA; 1B3; LOCALIZATION; IDENTIFICATION; PEPTIDES; OATP2B1; OATP3A1;
D O I
10.3389/fphar.2022.958023
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Organic anion transporting polypeptide 3A1 (OATP3A1, encoded by the SLCO3A1 gene) is a prostaglandin, oligopeptide, and steroid/thyroid hormone transporter with wide tissue distribution, expressed, e.g., in the human brain and testis. Although the physiological importance of OATP3A1 has not yet been clarified, based on its expression pattern, substrate recognition, and evolutionary conservation, OATP3A1 is a potential pharmacological target. Previously, two isoforms of OATP3A1, termed as V1 and V2, have been characterized. Here, we describe the cloning and functional characterization of a third isoform, OATP3A1_V3. The mRNA of isoform V3 is formed by alternative splicing and results in an OATP3A1 protein with an altered C-terminus compared to isoforms V1 and V2. Based on quantitative PCR, we demonstrate the widespread expression of SLCO3A1_V3 mRNA in human organs, with the highest expression in the brain and testis. By generation of an isoform V3-specific antibody and immunostaining, we show that the encoded protein is expressed in the human choroid plexus, neurons, and both germ and Sertoli cells of the testis. Moreover, we demonstrate that in contrast to isoform V1, OATP3A1_V3 localizes to the apical membrane of polarized MDCKII cells. Using HEK-293 cells engineered to overexpress OATP3A1_V3, we verify the protein's functionality and identify dehydroepiandrosterone sulfate as a novel OATP3A1 substrate. Based on their distinct expression patterns but overlapping functions, OATP3A1 isoforms may contribute to transcellular (neuro)steroid transport in the central nervous system.
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页数:12
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