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.
Highlights
It is well accepted that the effects of the various components of the renin-angiotensin system (RAS) range in various aspects of peripheral and brain functions well beyond those of regulating blood pressure and hydro-mineral balance
LINKING THE angiotensin type 2 (AT2) RECEPTOR WITH THE GROWTH FACTOR RECEPTORS Recently, we demonstrated that activation of Rap1/B-Raf/ p42/p44mapk pathway by the AT2 receptor was dependent on the nerve growth factor receptor TrkA, the mechanism involved remains unknown (Plouffe et al, 2006)
Since its identification in the early 90s, the AT2 receptor has been and still is shrouded by controversy, its low expression in the adult and its atypical signaling pathways adding to the challenge of studying this receptor
Summary
It is well accepted that the effects of the various components of the renin-angiotensin system (RAS) range in various aspects of peripheral and brain functions well beyond those of regulating blood pressure and hydro-mineral balance. In the early 1990s, our group observed that stimulation of the AT2 receptor with its selective agonist CGP42112A induces neurite outgrowth in the neuronal NG108-15 cell line (Laflamme et al, 1996), results that were further confirmed using the recently developed non-peptide selective AT2 receptor agonist C21/M024 (Wan et al, 2004) This effect was associated with an increase in mature neural cell markers, such as βIII-tubulin, and microtubule-associated proteins (MAPs) such as MAP2c (Laflamme et al, 1996), both known to stabilize tubulin in a polymerized state, participating actively in differentiation (Sanchez et al, 2000). This activation of p42/p44mapk by the AT2 receptor has been observed in non-neuronal COS-7 and NIH3T3 cells overexpressing the AT2 receptor (Hansen et al, 2000; De Paolis et al, 2002)
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