How does angiotensin AT2 receptor activation help neuronal differentiation and improve neuronal pathological situations?

Abstract

The angiotensin type 2 (AT2) receptor of angiotensin II has long been thought to be limited to few tissues, with the primary effect of counteracting the angiotensin type 1 (AT1) receptor. Functional studies in neuronal cells have demonstrated AT2 receptor capability to modulate neuronal excitability, neurite elongation, and neuronal migration, suggesting that it may be an important regulator of brain functions. The observation that the AT2 receptor was expressed in brain areas implicated in learning and memory led to the hypothesis that it may also be implicated in cognitive functions. However, linking signaling pathways to physiological effects has always proven challenging since information relative to its physiological functions has mainly emerged from indirect observations, either from the blockade of the AT1 receptor or through the use of transgenic animals. From a mechanistic standpoint, the main intracellular pathways linked to AT2 receptor stimulation include modulation of phosphorylation by activation of kinases and phosphatases or the production of nitric oxide and cGMP, some of which are associated with the Gi-coupling protein. The receptor can also interact with other receptors, either G protein-coupled such as bradykinin, or growth factor receptors such as nerve growth factor or platelet-derived growth factor receptors. More recently, new advances have also led to identification of various partner proteins, thus providing new insights into this receptor’s mechanism of action. This review summarizes the recent advances regarding the signaling pathways induced by the AT2 receptor in neuronal cells, and discussed the potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2 receptor activation by non-peptide and selective agonists could represent new pharmacological tools that may help to improve impaired cognitive performance in Alzheimer’s disease and other neurological cognitive disorders.

Structural basis for selectivity and diversity in angiotensin II receptors

“…Docking and molecular dynamics (MD) simulations suggest that helix VIII stabilizes the active-like conformation of the 7TM bundle of AT 2 R, while sterically blocking the binding of G proteins and β-arrestins (Fig. 2c), which is consistent with the lack of robust downstream signaling by AT 2 R as assessed by traditional G protein and β-arrestin assays 4,5 . In MD simulations, helix VIII not only remained in the range of positions within RMSD < 4 Å to the crystallographic structure for a total of 4 μs of unbiased simulation (Extended Data Fig.…”

“…AT 1 R is mainly responsible for blood pressure regulation, with several antagonists and inverse agonists approved for clinical use as anti-hypertensive drugs 3 . The function of AT 2 R, on the other hand, is less understood and remains controversial, with a growing number of studies suggesting that AT 2 R signals primarily via non-canonical, G protein- and β-arrestin-independent pathways 4,5 . In the cardiovascular system, AT 2 R has been reported to counteract several of the effects mediated by AT 1 R 6,7 , conferring cardioprotection.…”

Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

“…Mice were randomly allocated to treatment with vehicle (sterile isotonic saline), CGP42112A (Sigma Aldrich, St. Louis, MO, USA) an AT 2 agonist, which is a peptide with a short half-life [25], or PD 123319, an AT 2 antagonist [36,37]. CGP42112A was delivered in 1 of 3 doses: 0.1, 1.0, or 10.0 ng/kg/min [31].…”

“…However, CGP42112A is unlikely to be used as a therapeutic agent owing to undesired pharmacokinetics properties (e.g., a peptide with a short half-life) [25,27]. The nonpeptide AT 2 agonist compound 21, described by Wan et al [84], has a more favorable pharmacokinetic profile and may be more applicable to clinical treatment for TBI victims.…”

Vascular protective effects of Angiotensin Receptor Blockers: Beyond Blood pressure

“…While AT1R is widely expressed and mediates most inflammatory Ang-II effects, AT2R, is less expressed and has opposite effects, promoting vasodilation and anti-inflammatory effects [1] . Physiologically, AT2R actions are usually masked by the more abundant AT1R.…”