Binding Affinity of Some Endogenous and Synthetic TSPO Ligands Regarding the rs6971 Polymorphism

Int J Mol Sci. 2019 Jan 29;20(3):563. doi: 10.3390/ijms20030563.

Abstract

An intriguing target involved in several pathophysiological processes is the 18 kDa translocator protein (TSPO), of which exact functions remained elusive until now. A single nucleotide polymorphism in the TSPO gene influences the binding affinity of endogenous and synthetic TSPO ligands by facilitating a lower-affinity conformation, which modifies a potential ligand binding site, ultimately leading to a binding profile classification according to each genotype. For instance, some clinical effects of the distinctive binding affinity profile of cholesterol toward the TSPO of individuals with different genotypes have been extensively discussed. Therefore, we conducted an investigation based on a radioligand binding assay, to determine the inhibition constants of some reported endogenous TSPO ligands (diazepam binding inhibitor and protoporphyrin IX), as well as synthetic ligands (disulfiram and derivatives). We observed no dependency of the polymorphism on the binding affinity of the evaluated endogenous ligands, whereas a high dependency on the binding affinity of the tested synthetic ligands was evident.

Keywords: TSPO; binding affinity; diazepam binding inhibitor; disulfiram; protoporphyrin IX; radioligand; rs6971 polymorphism.

MeSH terms

  • Diazepam Binding Inhibitor / metabolism
  • Disulfiram / metabolism
  • Genotype
  • Healthy Volunteers
  • Humans
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding
  • Protoporphyrins / metabolism
  • Radioligand Assay
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism*

Substances

  • Diazepam Binding Inhibitor
  • Protoporphyrins
  • Receptors, GABA
  • TSPO protein, human
  • protoporphyrin IX
  • Disulfiram