• Angiotensin system;
  • AT4 receptor;
  • c-MET;
  • Epilepsy;
  • IRAP;
  • Memory;
  • LTD;
  • LTP

The central angiotensin system plays a crucial role in cardiovascular regulation. More recently, angiotensin peptides have been implicated in stress, anxiety, depression, cognition, and epilepsy. Angiotensin II (Ang II) exerts its actions through AT1 and AT2 receptors, while most actions of its metabolite Ang IV were believed to be independent of AT1 or AT2 receptor activation. A specific binding site with high affinity for Ang IV was discovered and denominated “AT4 receptor”. The beneficiary effects of AT4 ligands in animal models for cognitive impairment and epileptic seizures initiated the search for their mechanism of action. This proved to be a challenging task, and after 20 years of research, the nature of the “AT4 receptor” remains controversial. Insulin-regulated aminopeptidase (IRAP) was first identified as the high-affinity binding site for AT4 ligands. Recently, the hepatocyte growth factor receptor c-MET was also proposed as a receptor for AT4 ligands. The present review focuses on the effects of Ang II and Ang IV on synaptic transmission and plasticity, learning, memory, and epileptic seizure activity. Possible interactions of Ang IV with the classical AT1 and AT2 receptor subtypes are evaluated, and other potential mechanisms by which AT4 ligands may exert their effects are discussed. Identification of these mechanisms may provide a valuable target in the development in novel drugs for the treatment of cognitive disorders and epilepsy.