Huber Robert D, Gao Bo, Sidler Pfändler Marguerite-Anne, Zhang-Fu Wenting, Leuthold Simone, Hagenbuch Bruno, Folkers Gerd, Meier Peter J, Stieger Bruno
Univ. Hospital, Dept. of Internal Medicine, Institute of Clinical Pharmacology and Toxicology, 8091 Zurich, Switzerland.
Am J Physiol Cell Physiol. 2007 Feb;292(2):C795-806. doi: 10.1152/ajpcell.00597.2005. Epub 2006 Sep 13.
In the present study we isolated two splice variants of organic anion transporting polypeptide 3A1 (OATP3A1_v1 and OATP3A1_v2) from human brain. OATP3A1_v2 lacks 18 amino acids (aa) at the COOH-terminal end (692 aa) but is otherwise similar in sequence to OATP3A1_v1 (710 aa). OATP3A1_v1 exhibits a wide tissue distribution, with expression in testis, various brain regions, heart, lung, spleen, peripheral blood leukocytes, and thyroid gland, whereas OATP3A1_v2 is predominantly expressed in testis and brain. On the cellular and subcellular levels OATP3A1_v1 could be immunolocalized in testicular germ cells, the basolateral plasma membrane of choroid plexus epithelial cells, and neuroglial cells of the gray matter of human frontal cortex. Immunolocalization of OATP3A1_v2 included Sertoli cells in testis, apical and/or subapical membranes in choroid plexus epithelial cells, and neurons (cell bodies and axons) of the gray and white matter of human frontal cortex. The rodent ortholog Oatp3a1 was also widely distributed in rat brain, and its localization included somatoneurons as well as astroglial cells. Transport studies in cRNA-injected Xenopus laevis oocytes and in stably transfected Chinese hamster ovary FlpIn cells revealed a similar broad substrate specificity for both splice variants. Transported substrates include prostaglandin (PG)E(1) and PGE(2), thyroxine, and the cyclic oligopeptides BQ-123 (endothelin receptor antagonist) and vasopressin. These studies provide further evidence for the involvement of OATPs in oligopeptide transport. They specifically suggest that OATP3A1 variants might be involved in the regulation of extracellular vasopressin concentration in human brain and thus might influence the neuromodulation of neurotransmission by cerebral neuropeptides such as vasopressin.
在本研究中，我们从人脑中分离出有机阴离子转运多肽3A1的两种剪接变体（OATP3A1_v1和OATP3A1_v2）。OATP3A1_v2在COOH末端（692个氨基酸）缺少18个氨基酸（aa），但在序列上与OATP3A1_v1（710个氨基酸）相似。OATP3A1_v1表现出广泛的组织分布，在睾丸、各个脑区、心脏、肺、脾脏、外周血白细胞和甲状腺中均有表达，而OATP3A1_v2主要在睾丸和脑中表达。在细胞和亚细胞水平上，OATP3A1_v1可免疫定位在睾丸生殖细胞、脉络丛上皮细胞的基底外侧质膜以及人额叶皮质灰质的神经胶质细胞中。OATP3A1_v2的免疫定位包括睾丸中的支持细胞、脉络丛上皮细胞的顶端和/或亚顶端膜以及人额叶皮质灰质和白质中的神经元（细胞体和轴突）。啮齿动物直系同源物Oatp3a1在大鼠脑中也广泛分布，其定位包括躯体神经元以及星形胶质细胞。在注射了cRNA的非洲爪蟾卵母细胞和稳定转染的中国仓鼠卵巢FlpIn细胞中的转运研究表明，两种剪接变体具有相似的广泛底物特异性。转运的底物包括前列腺素（PG）E(1)和PGE(2)、甲状腺素以及环寡肽BQ-123（内皮素受体拮抗剂）和加压素。这些研究为OATP参与寡肽转运提供了进一步的证据。它们特别表明，OATP3A1变体可能参与人脑中细胞外加压素浓度的调节，从而可能影响诸如加压素等脑神经肽对神经传递的神经调节作用。
