Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Abstract

Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.

The 5′-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2

“…In contrast, expression of the creatine transporter (SLC6A8) was decreased by AMPK and PKC activation (Li et al, 2010), and we found previously that OATP1A2 trafficking was regulated by PKC and CKII (Fig. 6) (Zhou et al, 2011;Chan et al, 2016;Murray and Zhou, 2017). Similar to AMPK inhibition, PKC activation accelerated the internalization of OATP1A2.…”

“…4B). As for the previous reports, the protein trafficking of OATPs is also facilitated by other chaperon proteins, such as PDZ-domain containing proteins (Zheng et al, 2014;Murray and Zhou, 2017;Ferreira et al, 2018); therefore, it is plausible that AMPK inhibition impacts on chaperon proteins and indirectly influences the expression and function of OATP1A2. Further studies to explore the impact of AMPK inhibition on these chaperon proteins and the potential atypical AMPK motifs in OATP1A2 are now warranted.…”

Interindividual Diversity in Expression of Organic Anion Uptake Transporters in Normal and Cirrhotic Human Liver

“…As OATP2B1 and NTCP are localized to two different chromosomes (11 and 14, respectively), the possibility of common regulatory mechanisms related to trans‐acting factors that interact with DNA–protein binding domains or posttranscriptional regulation of messenger RNA stability by binding to an element on the RNA molecule should be considered. Although candidate factors have been suggested, ( 15,35,36 ) further investigation will be required to elucidate the importance of these potential regulatory mechanistic components.…”

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions

“…At the post-translational level, both OATP1B1 and OATP1B3 have been reported to be glycosylated proteins [ 3 , 121 ]. N-linked glycosylation at asparagine (Asn) residues are important for the regulation of membrane transporters such as OATP1B1 and 1B3 [ 122 ]. Briefly, oligosaccharides are added to the asparagine residues by oligosaccharyl-transferase enzymes [ 122 ].…”