Abstract
Two main isoforms of the Translocator Protein (TSPO) have been identified. TSPO1 is ubiquitous and is mainly present at the outer mitochondrial membrane of most eukaryotic cells, whereas, TSPO2 is specific to the erythroid lineage, located at the plasma membrane, the nucleus, and the endoplasmic reticulum. The design of specific tools is necessary to determine the molecular associations and functions of TSPO, which remain controversial nowadays. We recently demonstrated that TSPO2 is involved in a supramolecular complex of the erythrocyte membrane, where micromolar doses of the classical TSPO ligands induce ATP release and zinc protoporphyrin (ZnPPIX) transport. In this work, three newly-designed ligands (NCS1016, NCS1018, and NCS1026) were assessed for their ability to modulate the functions of various erythrocyte’s and compare them to the TSPO classical ligands. The three new ligands were effective in reducing intraerythrocytic Plasmodium growth, without compromising erythrocyte survival. While NCS1016 and NCS1018 were the most effective ligands in delaying sorbitol-induced hemolysis, NCS1016 induced the highest uptake of ZnPPIX and NCS1026 was the only ligand inhibiting the cholesterol uptake. Differential effects of ligands are probably due, not only, to ligand features, but also to the dynamic interaction of TSPO with various partners at the cell membrane. Further studies are necessary to fully understand the mechanisms of the TSPO’s complex activation.
Highlights
We recently demonstrated that TSPO2, voltage dependent anion channel (VDAC), and adenine nucleotide transporter (ANT) are present in the detergent-resistant domains of the erythrocyte membrane [5]
We have compared the effects of the classical ligands (PK 11,195, Ro5-4865, and SSR-180,575), against three imidazoquinazolinone-derivative, newly synthetized Translocator Protein (TSPO) ligands (NCS1016, NCS1018, and NCS1026 [28]), and studied their effects on the main functions identified for erythrocyte TSPO2, which include the release of intracellular ATP [27], uptake of the heme analog ZnPPIX [5], and P. falciparum growth [5,29], as well as cholesterol uptake
This is important as TSPO ligands can display different affinities when interacting directly with TSPO [9,22,23,39], or the interface of TSPO and partner proteins, such as VDAC and ANT [24,25]
Summary
Translocator Protein (TSPO) is an 18 kDa ubiquitous transmembrane protein, previously known as the Peripheral Benzodiazepine Receptor (PBR), described as an alternative binding site for benzodiazepines, which is different from the central nervous system’s binding site [1,2]. We have compared the effects of the classical ligands (PK 11,195, Ro5-4865, and SSR-180,575), against three imidazoquinazolinone-derivative, newly synthetized TSPO ligands (NCS1016, NCS1018, and NCS1026 [28]), and studied their effects on the main functions identified for erythrocyte TSPO2, which include the release of intracellular ATP [27], uptake of the heme analog ZnPPIX [5], and P. falciparum growth [5,29], as well as cholesterol uptake These new TSPO ligands have shown higher or lower effect, compared to classical ligands, depending on the analyzed function. The study of the newly synthetized TSPO ligands presented, reveals a path forward on the study and modulation of TSPO functions, in which the fine-tuning of ligand-protein interactions appears as a crucial point in controlling the modulation of the protein’s or protein complex’s function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
