The beta1-adrenergic receptor in the heart

Abstract

beta1-adrenergic receptor (β₁-AR) belongs to G protein-coupled receptors, regulating cardiac physiological and pathological process through complex signaling pathways. Physiologically, the activation of β₁-AR produces positive chronotropic, positive inotropic and positive dromotropic effects in the heart. However, excessive or sustained activation of β₁-AR can cause myocardial injury, arrhythmias, and heart failure. The β₁-AR in the heart exhibits tissue-specific distribution patterns and subcellular localization features adapted to its function within cardiomyocytes. Upon ligand binding, the β₁-AR undergoes conformational changes and transmits signaling through G protein-dependent pathways (β₁-AR/Gs and β₁-AR/Gi) as well as a G protein-independent pathway (β₁-AR/β-arrestin) to regulate cardiac activity. Subsequently, the β₁-AR can either dissociate from G protein to undergo desensitization and terminate signal transduction, or it can be endocytosed into the cell, transported to the lysosome to be degraded, or returned to the plasma membrane to continue its function. Additionally, it has been found that β₁-AR can cause or exacerbate heart disease when abnormal changes occur in its distribution density, localization, and mediated downstream signaling pathways. Therefore, β₁-AR represents an important pharmacotherapeutic target for the treatment of cardiac diseases. Among the relevant therapeutic agents, β₁-AR blockers designed specifically against β₁-AR have evolved to the third generation. This review comprehensively analyzes β₁-AR from perspectives including its research history, expression, and distribution in the heart, protein structure, signaling pathways, and associations with cardiac diseases.

Fig. 1. Causes of decreased β₁-AR expression in heart failure.

Reduced gene transcription capacity and enhanced protein degradation both lead to the downregulation of β₁-AR expression. (Created with BioRender.com).

Fig. 2. Distribution of β₁-AR in the heart and cardiomyocytes.

The distribution of β₁-AR in the heart is mostly concentrated around the sinus node. In cardiomyocytes, β₁-ARs localize to structures with double-membrane architectures, including T-tubules, SR, Golgi apparatus, and the nuclear envelope. (Created with BioRender.com).

Fig. 3. Schematic diagram of the signaling pathway after binding of β₁-AR to Gs proteins.

Upon activation of β₁-AR by NE, the receptor couples with Gs protein, leading to dissociation into Gαs and Gβγ subunits. Subsequently, the Gαs subunit activates AC, which catalyzes the hydrolysis of ATP to cAMP. The downstream effectors of cAMP include Epac and PKA. Epac can affect the release of calcium ions from the Golgi apparatus and mitochondria through the PLC/CaMKII pathway. MAO-A on mitochondria inhibits β₁-AR signaling and PKA activity on the SR. PKA modulates calcium ion release and reuptake at the SR by phosphorylating RyR, PLN, and SERCA2a, and enhances myocardial contractility by phosphorylating cMyBP-C. In heart failure, β₁-AR is over-activated. PKA activity is reduced. ROS production is increased. an increased production of ROS. These molecular alterations exacerbate inflammatory responses and myocardial fibrosis. Enhanced activity of MAO-A further inhibits PKA, thus forming a vicious cycle. As a result, the activity of cMyBP-C decreases, myocardial contractility declines, and myocardial damage continues to worsen. (Created with BioRender.com).

Fig. 4. β₁-AR couples with Gi proteins in the presence of carvedilol.

There are two signaling pathways after binding of β₁-AR to Gi protein: 1) β-arrestin/EGFR/ERK pathway; 2) β₁-AR/Gi/PI3K/Akt/NOS3/cGMP/PKG pathway. Both pathways exert cardioprotective effects. (Created with BioRender.com).

Fig. 5. Schematic representation of the effects following the binding of β₁-AR to β-arrestin.

Phosphorylated β₁-AR dissociates G proteins by recruiting β-arrestin. Subsequently, β₁-AR no longer transduces signals through the AC/Gs/cAMP signaling pathway, which is termed “desensitization”. The desensitized β₁-AR can still recruit Raf, Src, and EGFR under the action of β-arrestin, thereby activating downstream signaling pathways and exerting protective effects on the heart. Additionally, β-arrestin also mediates the endocytosis of β₁-AR. Facilitated by the TGN, β₁-AR can either be routed to the lysosomes for degradation or be recycled back to the cell membrane to resume its function. The binding of β-arrestin to β₁-AR prevents overactivation of β₁-AR. Through endocytosis, this interaction can also maintain a relatively constant number of β₁-AR receptors on the cell membrane. (Created with BioRender.com).

Fig. 6. Schematic illustration of the association of β₁-AR with different heart diseases.

From cardiomyocytes apoptosis to heart failure, β₁-AR affects cardiac diseases at different stages through distinct mechanisms. (Created with BioRender.com).

Fig. 7. Development and differentiation of β₁-AR blockers.

The adverse effects of first-generation β-AR blockers, particularly bronchoconstriction and metabolic dysregulation, motivated the development of second-generation selective β₁-AR blockers. Subsequently, third-generation selective β₁-AR blockers have been designed to possess vasodilatory properties, optimizing their hemodynamic profile. Furthermore, the structural schematic diagram of the representative drugs of three generations of β₁-AR blockers (metoprolol, nebivolol, propranolol) is presented. The common structure marked in pink in the figure is aryloxypropanolamine. (Created with BioRender.com).