Abstract
The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and its implication in metabolic regulation. This coincides with the recent development and marketing of agonists at the human receptor with superior specificity. Twenty years ago, however, we and others described the expression of β3-AR in human myocardium and its regulation of contractility and cardiac remodeling. Subsequent work from many laboratories has since expanded the characterization of β3-AR involvement in many aspects of cardiovascular physio(patho)logy, justifying the present effort to update current paradigms under the light of the most recent evidence.
Highlights
Beta3-adrenergic receptors (β3-AR) have traditionally been considered as metabolic receptors in the adipose tissue
By decreasing cardiac myocyte contractility through eNOS/cGMP signaling in human myocardial biopsies [13], as confirmed in cardiac tissue from the transgenic mouse model with cardiac-specific expression of the human β3-AR [14]; a similar conclusion was drawn from observations of the converse effect in myocytes from β3-AR−/− mice [24]
Based on the evidence reviewed in the previous sections, β3-AR represent a promising therapeutic target for the treatment or prevention of cardiovascular diseases (CVD), be it through their systemic or direct activation in cardiac myocytes, in particular given their increased expression in the pathological myocardium [15]
Summary
Beta3-adrenergic receptors (β3-AR) have traditionally been considered as metabolic receptors in the adipose tissue. 50–40% of amino-acid sequence homology with β1 and β2-AR, respectively, with main divergences located in the third intracellular loop and C-terminal tail The latter contains a S-palmitoylation canonical site on Cys361/363 , shared by the all β-ARs, involved in G-protein coupling and AC activation in β1/β2AR. Using a transgenic mouse model expressing the human β3-AR in cardiac myocytes together with a FRET-based cGMP biosensor, our group further showed that β3-AR co-localized with caveolin-3 and eNOS in caveolae-enriched rafts, and directly coupled to sGC/cGMP signaling [22] (Figure 1A) Such co-localization was confirmed in experiments combining a similar cGMP biosensor with scanning ion conductance microscopy (SICM) that further identified functional β3-AR to be confined to the T-tubules in healthy rat cardiac myocytes [23]. Coupling of β3-AR to nNOS (upregulated in hypertrophic myocardium) will exert additional antioxidant effects through inhibition of Xanthine Oxidoreductase (XOR), resulting in protection of residual eNOS from oxidative uncoupling
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