Targeting β3-Adrenergic Receptors in the Heart: Selective Agonism and β-Blockade

Figures

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  FIGURE 1.. Human β3AR structure. Shown here is the structure of the human β3AR. The receptor is a GPCR with 7-TMDs, an extracellular N-terminal domain (exD1), and an intracellular C-terminal domain (inD4). The receptor presents also 6 loops, 3 are intracellular (inD1, inD2, and inD3), and 3 are extracellular (exD2, exD3, and exD4). Indicated with arrows are the asparagine (N) residues, in the exD1, that are sites of N-glycosylation; tryptophan (W) in position 64 that is the location of β3AR-polymorphism (Trp64Arg) and the cysteine (C) in position 361 that is a site subjected to palmitoylation.

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  FIGURE 2.. Multiple alignment of mammalian β3AR. Protein sequence alignment of mouse, dog, pig, human, and Macaca mulatta β3AR. The TMD is highlighted in yellow; the tryptophan (W) in position 64 is in red; the cysteine (C) in position 361 is in green.

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  FIGURE 3.. Multiple alignment of human βARs. Protein sequence alignment of human β1, β2, and β3AR. The TMD is highlighted in yellow.

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  FIGURE 4.. Schematic representation of β3AR signaling activation in cardiomyocytes. β3ARs are coupled to both stimulatory G proteins (Gs) and inhibitory G proteins (Gi). Although the Gs pathway induces the generation of cAMP and cGMP which, in turn, activates the PKA and PKG, respectively, the activation of Gi signaling pathway is able to stimulate only the generation of cGMP and the activation of PKG. PKA has multiple roles in cardiomyocytes and is able to induce the phosphorylation of several key factors involved in the regulation of contractility, such as cardiac troponin I (cTnI) and phospholamban (PLN). The latter affects Ca2+ cycling to the contractile proteins. Furthermore, PKA can phosphorylate the L-type Ca2+ channel (LTCC) increasing the influx of extracellular Ca2+. Importantly, PKA can also activate protein kinase B (Akt) with the subsequent activation of the endothelial NO synthase (eNOS). Of note, eNOS activation increases the generation of NO which, in turn, activates the soluble guanylate cyclase to produce cGMP and PKG activation. Similar to PKA, PKG is able to phosphorylate PLN and cTnI. However, PKG can induce the inactivation of LTCC, thus reducing the extracellular Ca2+…