all trans retinoic acid br Under normal physiological condit

Under normal physiological conditions, the agonist binds to AT1R on the surface of the plasma membrane and activates the receptor, mediating downstream signaling. Then, activated AT1R is phosphorylated by protein kinase C (PKC) [13] or G protein coupled receptor kinases (GPKs, such as GRK2 [13], GRK4 [14] and GRK5 [15]), which can promote the separation of G proteins from receptors and thereby terminate signal transduction. At the same time, GRK-mediated receptor phosphorylation can facilitate the translocation and binding of β-arrestins to the receptor. Via their association with the β2-adaptin subunit of the adaptor (or assembly) protein-2 (AP-2) heterotetrameric adaptor complex, β-arrestins target GPCRs to clathrin-coated pits [16]. There are three stages to the formation of clathrin-coated vesicles: (1) coated pits form; (2) coated pits become invaginated; and (3) the coated vesicles pinch off [17] (Fig. 1). The coated vesicles that pinch off from the plasma membrane are then targeted to and fuse with GTP-binding protein 5 (Rab5)-positive endosomes to form early endosomes in a process called endocytosis [16–18] (Fig. 2). Some AT1R endocytosed into the cytoplasm can recycle to the plasma membrane to maintain the density of the receptor on the plasma membrane, which is called recycling [19]. There are two all trans retinoic acid of GPCRs according to their affinity for β-arrestins. “Class A" GPCRs (e.g., β2-adrenergic receptor [β2AR]) interact with β-arrestins transiently and recycle rapidly back to the plasma membrane; they are mainly regulated by GTP-binding protein 4 (Rab 4) [20,21]. In contrast, “Class B” GPCRs (e.g., vasopressin type 2 receptor [V2R]) bind tightly to β-arrestins and are recycled slowly back to the plasma membrane; they are mainly regulated by GTP-binding protein 11 (Rab 11) [22,23]. AT1R, a typical “Class B” GPCR, is recycled slowly back to the plasma membrane and its recycling is regulated by Rab11 [24,25]. However, the current study suggests that Rab4 and Rab11 are involved in regulating AT1R recycling [19] (Fig. 2). Some functional or structural damaged receptors are delivered to late endosomes, where they fuse with lysosomes to be degraded. This process is regulated by GTP-binding protein 7 (Rab 7) [16] (Fig. 2). In addition to the clathrin endocytosis pathway, AT1R can be endocytosed via caveolae-dependent pathways. Caveolae are membrane invaginations with a diameter of 60–80 nm. They are composed of cholesterol, glycosyl sphingomyelin, sphingomyelin, and some structural proteins such as caveolin [26,27]. Caveolin-1 is the main constituent of caveolae; it is indirectly coupled to cytoskeleton proteins to maintain the caveolae retraction morphology [28]. The caveolae bud into the cell when stimulated by various agents known as endocytic caveolar carriers, which is regulated by dynamin [29,30], PKC [31], and tyrosine kinases such as Src kinases [32]. Then, the caveolar carriers can fuse with the caveosome in a Rab5-independent manner or with early endosomes in a Rab5-dependent manner. Similarly, they can be recycled to the plasma membrane after endocytosis [33,34]. As mentioned above, receptor internalization maintains the dynamic balance of the receptor on the plasma membrane [16]. When the receptor is exposed to agonist for a long time, the AT1R endocytosis rate is higher than the rate of recycling. This means that the cell membrane surface density of AT1R is reduced, and simultaneously intracellular AT1R levels are increased, which is considered an increase in receptor internalization. The increased receptor internalization reduces the likelihood of the receptor and agonist recombining on the plasma membrane, thus reducing the sensitivity of the receptor to agonists in a phenomenon known as AT1R tachyphylaxis [35] or desensitization. In other words, receptor desensitization is to some extent achieved by its internalization.