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

Autor: Alessandro Cannavo, Walter J. Koch
Přispěvatelé: Cannavo, Alessandro, Koch, Walter J.
Rok vydání: 2017
Předmět:
Zdroj: Journal of Cardiovascular Pharmacology
ISSN: 0160-2446
Popis: G protein–coupled receptors (GPCRs) are nodal regulators of mammalian cell physiology because they transduce cell signals from diverse ligands such as neurohormones, sensory stimuli, and ions through heterotrimeric G proteins.1 In the heart, they represent the major modulators of both function and morphology with β-adrenergic receptors (βARs) representing “the heads of the line”, and for this reason they are considered the most important molecular targets in the cardiovascular system.2–4 Currently, 3 βAR subtypes (β1AR, β2AR, and β3AR) have been identified in the myocardium, with β1 and β2ARs the most expressed and studied.5–7 However, since its discovery in 1989,7 it soon seemed clear that β3ARs, the isoform with minor expression, can influence cardiovascular physiology. In particular, β3ARs seem to have multiple roles that go from regulation of metabolism,8,9 vasodilation, and relaxation8 to cardiac contractility.9 Thus, this receptor is of high interest especially for new potential therapeutic approaches for heart disease. In this review, we will discuss what is known about the cardiac role of β3ARs and how not only their activation but also the blockade could be beneficial or not in cardiac physiology and in disease. β3-Adrenergic Receptor (β3AR) Structure The mammalian β3AR sequence consists of about 400–408 amino acids in a protein that has the typical structure of all GPCRs.10 The β3AR has 7 transmembrane domains (7-TMDs) with an extracellular N-terminal that is glycosylated, and an intracellular C-terminal domain.10 Further, the Cys361 residue in the fourth intracellular domain is palmitoylated, a feature that has been shown to be associated with G protein-coupling and adenylyl cyclase stimulation following agonist stimulation of the receptor11 (Fig. ​(Fig.1).1). As shown in Figure ​Figure2,2, the protein sequence alignment between different mammalian species demonstrates that most of the homology between the β3AR amino acid sequences is concentrated in the 7-TMDs and in the membrane-proximal regions of the intracellular loops. Interestingly, when the β3AR protein sequence is compared with other βAR (β1 and β2AR) isoforms, it is still possible to observe a high level of homology in the 7-TMD sequence, but a significant divergence is present both in the third intracellular loop and in the C-terminal domain (Fig. ​(Fig.3).3). This difference probably represents the major factor affecting the pharmacologic regulation of the receptors and their response to a ligand. In this regard, the C-terminus of both β1 and β2ARs is rich in serine and threonine residues, and is subjected to GPCR kinase (GRK)-mediated regulation through phosphorylation.10 Further, these receptors also harbor a consensus sequence for protein kinase A (PKA).10 Of note, the β3AR lacks all of these sites, and is more resistant to agonist-induced desensitization/downregulation. Finally, these sequence divergences also support differential and intracellular signaling (including G protein-coupling) between the 3 βAR isoforms, which may determine their relative roles in physiology and in the disease. Open in a separate window 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.
Databáze: OpenAIRE
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