The majority of skin cancers are caused by over exposure to ultraviolet (UV) radiation. The effects of UV radiation on the expression of drug transporters expressed in human skin has never been studied. In this the effects of UVA and UVB irradiation on the expression of ATP-binding cassette (ABC) transporters and Solute carrier (SLC) transporters was evaluated in normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF) in primary culture. First experiments were intended to validate the inflammatory reaction in response to stimulation by lipopolysaccharide (LPS) in NHEK, NHDF and 3D-reconstructed human epidermis (3D-RHE) model. LPS treatment has shown to increase the expression of IL-8 and TNF-alpha in all three in vitro models. Expression of the most expressed ABC and SLC transporters was then measured in NHEK and NHDF after UVA (30 J/m²) and UVB (40 mJ/m²) irradiation. The most striking result was a significant 29-fold increase of the expression of SLCO4A1 in normal human dermal fibroblasts. In summary, this study shows for the first time a significant regulation of the expression of SLCO4A1 in human dermal fibroblasts induced by UVA irradiation. This finding is of particular interest as most of skin cancers are caused by over exposure to ultraviolet radiation and need to be considered in pharmacokinetic evaluation of topical drugs.

Solute carrier (SLC) proteins transport a wide range of substrates across biological membranes and more than 400 proteins are considered as SLCs based on its sequence. Despite it has important potential applications in drug development, the SLC superfamily is still understudied. Drosophila blot, an orphan SLC protein, regulates F-actin organization in the syncytial blastoderm and the Malpighian tubules. However, the molecular mechanism was unknown. In this study, we found Blot was localized at the furrow canal, the front of the invaginating membrane during cellularization process. Blot is required for maintaining proper morphology of furrow canal and cellularization process. By affinity purification and mass spectrometry we identified RhoGEF ELMO/DOCK complex was required for Blot-mediated F-actin organization and cellularization. Further analysis revealed that ELMO localization depends on Blot. Taken together, we propose Blot plays a role in F-actin organization as an upstream factor of ELMO by recruiting ELMO to the target membrane compartments.

Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It has been early on recognized that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical composition has recently been used as a means to enhance their targeting or absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.

Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical mitochondrial carrier family SLC25, the past decade led to the discovery of additional protein families that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins and mitochondrial cation/H+ exchangers that have been linked to vital physiological functions and disease. Their structures and transport mechanisms are still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combined sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanism and structure of these novel mitochondrial carriers.