Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS

Abstract

Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood-brain barrier, the choroid plexus, and other organs. The physiologic function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed. We therefore investigated the human retina for the expression of OATP1A2 and OATP2B1 and extended the study to human brain. Furthermore, we searched for peptide neurotransmitters as novel OATP substrates. OATP1A2 displayed a broad expression pattern in human retina as assessed by immunofluorescence localization. It is expressed in photoreceptor bodies and somas of amacrine cells. OATP1B2 expression is restricted to the inner nuclear layer and to the inner plexiform layer. Using paraffin sections from human cortex, cerebellum, and hippocampus, OATP1A2 was localized to neurons and neuronal processes, while OATP2B1 is expressed in endothelial cells of brain capillaries. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 and OATP2B1. Doublelabeling immunofluorescence of human retina demonstrated the presence of substance P and of vasoactive intestinal peptides in neurons expressing OATP1A2 and OATP2B1, respectively. The expression of OATP1A2 and OATP2B1 in retinal neurons implies a role of these transporters in the reuptake of peptide neurotransmitters released from retinal neurons. The abundant expression of OATP1A2 in brain neurons points to the possibility that OATP1A2 could be involved in the homeostasis of neurosteroids. The high expression of OATP2B1 in brain capillaries supports an important function of OATPs in substance penetration across the blood-brain barrier. Order of Authors Secondary Information:Abstract: Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood brain barrier, the choroid plexus and other organs. The physiologic function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed. We therefore investigated the human retina for the expression of OATP1A2 and OATP2B1 and extend the study to human brain. Furthermore, we searched for peptide neurotransmitters as novel OATP substrates. OATP1A2 displayed a broad expression pattern in human retina as assessed by immunofluorescence localization in fixedfrozen section. It is expressed in photoreceptor bodies and somas of amacrine cells. OATP1B2 expression is restricted to the inner nuclear layer and to the inner plexiform layer. Using paraffin sections from human cortex, cerebellum and hippocampus, OATP1A2 was localized to neurons and neuronal processes, while OATP2B1 is expressed in endothelial cells of brain capillaries. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 and OATP2B1. Doublelabeling immunofluorescence of human retina demonstrated the presence of substance P and of vasoactive intestinal peptides in neurons, which express OAT...

Solute Carrier Family of the Organic Anion-Transporting Polypeptides 1A2– Madin-Darby Canine Kidney II: A Promising In Vitro System to Understand the Role of Organic Anion-Transporting Polypeptide 1A2 in Blood-Brain Barrier Drug Penetration

“…The physiologic expression data would help us to contextualize the current in vitro findings, as has been previously done for P-gp (Uchida et al, 2011a(Uchida et al, , 2014. The data could also shed light on the emerging debate on neuronal (Gao et al, 2014) and more widely accepted brain endothelial localization (Gao et al, 2000;Bronger et al, 2005;Lee et al, 2005;Kalvass et al, 2013).…”

“…It was later confirmed to be expressed on the luminal membrane of the BBB in tumorous and healthy adjacent tissue (Bronger et al, 2005), although a more recent paper reports expression in neurons as well (Gao et al, 2014). OATP1A2 transports amphipathic substrates, including bile salts, thyroid hormones, steroid conjugates, organic dyes, and anionic oligopeptides as well as xenobiotics (Franke et al, 2009).…”

Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2

“…18 Overall, these transporters mediate the cellular influx of structurally diverse compounds and greatly impact on the pharmacokinetics of drugs in body. Drugs and endogenous substances competing for SLC transporters have also been widely reported, [19][20][21] and can significantly impact on therapeutic outcomes and toxicities. To date, the interactions between SLC transporters and CQ or HCQ remain unclear.…”

Functional Characterization of Carrier-Mediated Transport of Pravastatin across the Blood-Retinal Barrier in Rats

“…OATP1A2 and OAT3 are expressed in human retina/choroid at the mRNA level (Chan et al, 2015), as well as at the BBB (Cha et al, 2001;Gao et al, 2015). In addition, both transporters recognize pravastatin (Takeda et al, 2004;Shirasaka et al, 2010).…”