Introduction

Cardiovascular diseases include the heart and blood vessel; others are stroke, cardiomyopathy, congenital heart disease, and hypertension, and these are the leading causes of death in America [1]. Heart failure is associated with impaired cardiac vagal responsiveness [2] and it is common and costly to manage. It was assumed that there is a total of 1–3% of health care expenditure in North America, Western Europe, and Latin America with 5% complications in the adult patients admitted in US and European hospitals [3]. Heart failure is a progressive CVD with a rapidly growing public health problem and is the leading cause of mortality and morbidity with over 26 million people worldwide and more than 14 million people in Europe [4, 5] and nearly 8.26 million Americans having 32.8% of the cardiovascular-related deaths [6]. It was revealed that heart failure (HF) contributed to approximately 5% of all deaths in the UK [7]. It was also suggested that 30% of patients diagnosed have HF and chronic obstructive airway disease (COPD) [8]. β-Adrenergic receptors (βARs) are a member of the superfamily of G protein–coupled receptors (GPCRs); it is involved in the regulation of physiological processes such as hormonal homeostasis, metabolism, cell growth, and sensory perception [9]. GPCRs are membrane protein and their structural determination, purification, expression, and crystallization help in new drug discovery [10, 11]. It is the largest single family of proteins and is made up of 4% of those coded by the human genome. The most important of GPCR means of technology is the structure-based design of agonist and antagonist ligands which helps to determine the design of new ligands [12, 13]. Reports showed that about 50–60% of all existing medicines are believed to target GPCRs [14].

There are several subtypes of βARs including β1, β2, and β3. β1 and β2 are vital in the regulation of excitation-contraction coupling of a myocardium. However, the β1AR comprises 75–80% of βARs found in the heart. β2AR is expressed in the kidney, lung, and blood vessel and also in the heart and comprises 20–25% of cardiac βARs while β3AR is found in the adipose tissue and very little amount in the heart [15]. β-Adrenergic receptors play a major role in the cardiac functions via signaling transduction controlled by the G protein–coupled receptor kinase (GRK) phosphorylation interactions. The therapeutic capability of a βAR in disease regulation such as cardiovascular diseases (CVDs) is of great importance [16, 17]. When the cardiac βAR signaling is not functioning properly, the circulation of epinephrine levels and downregulation which are expressed on the cardiac myocytes can increase [18]. The continuous activation of the adrenergic receptor is capable of contributing to HF pathogenesis [19]. GPCR signaling pathways are the major prescription for CVD because ligand binding induces conformation changes in the GPCR that could disrupt the interaction of ions between a third cytoplasmic loop and a sixth transmembrane segment, and this brings about coupling with heterotrimeric G protein composed of three subunits: α, β, and γ [20]. The three subtypes of βARs are coupled to Gαs and cyclic AMP (CAMP)–related pathways, and it is signaling to proceed through G protein–independent mechanism [21]. It is reported that βAR activation stimulates adenylyl cyclase (AC) activity through G proteins which enhance the formation of CAMP in the myocardium [22]. Ligands can bind to a targeted site through the extracellular face in the center of the seven helices of hydrogen bonding or charged residue to interact with the natural ligand [23]. The binding effect is because the adrenergic receptor superfamily is a member of the G protein–coupled receptor, which is a membrane receptor that can activate heterotrimeric G proteins. However, signaling by GPCR is normally interfered and disrupted by the GRKs. Moreover, GRKs play a major role in the regulation of adrenergic responses via a mechanism independent from G proteins.

The aging in cardiac βAR response is a result of the downregulation of β1AR, and a decreased sensitivity of βARs by isoproterenol enhances conformational changes in the catecholamine-stimulated AC activity in the cardiovascular system (CVS) [24]. The current effective treatments of CVDs have been developed in a diverse approach called drug therapy [25]. Apart from drug therapy, some classes of the molecule were fully developed as an alternative to replace skeletal and cardiovascular systems. Few of the approved drug therapy are very effective in the treatments of cardiovascular disease [26]. The main aim and objective of this review will focus on evaluating the capability of βARs associated with cardiovascular diseases.

βARs in heart failure

The failing of the human heart is adrenergically hyperactivated which determines the cardiac functions/performance [27, 28]. Heart failure is a large pathophysiological syndrome which results from the primary defect that identified the capability of the heart to fill or eject blood appropriately [29]. The human β2AR is expressed in the pulmonary and cardiac myocyte tissues and is a therapeutic target for asthma and heart failure [30]. βARs remain a major regulator of cardiac function out of over 200 GPCRs in the heart [31]. The continuous/increased activation of adrenergic in the failing heart helps to maintain cardiac function, but the chronic adrenergic stimulation contributes to myocardial dysfunction and ventricular remodeling.

The aging process also induces structural and functional changes including myocyte hypertrophy and subsequent increase in myocardial fibrosis, wall thickness, and extracellular matrix remodeling with diastolic dysfunction via reduced active fillings of the left ventricle [32]. In the interface between sympathetic nervous system (SNS) and CVS, βARs control the progression of HF and any unnecessary changes in βAR signaling which will result in the reduction of the β1AR level to half and a sharp increase of the Gα level, and this will elevate βARK1 functions [9].

An exciting role of sympathetic activation in HF due to elevated myocardial βARK1 level and βAR desensitization in the dysfunctional heart is called protective mechanisms; such mechanisms will worsen the physiological deterioration caused by excess catecholamine stimulation, and chronic use of β-agonists in the HF is harmful [33]. β1AR third intracellular loop consists of the phosphorylation motif for basophilic protein kinase C (PKC) and phosphorylation attributed to protein kinase A (PKA). Catecholamines help the heart to perform its function by activating cardiac βAR [34]. If there is persistent activation of the adrenergic receptor by chemical or biological effects, myocardial damages such as cardiac hypertrophy, fibrosis, and apoptosis can be induced [35]. β2AR stimulation determines the antiapoptotic cardiac outcomes in the heart [36]. However, cardiac hypertrophy is the leading cause of HF, and once cardiac hypertrophy develops, it progressed to heart failure. βAR stimulation increases oxidative stress in the heart and cerebral artery, and it can induce different cytoskeletal and functional modifications through modification of several parts of the βAR signaling transduction pathways. The cardiac dysfunction due to stimulation of βARs induces vascular dysfunction by the disruption of the actin cytoskeleton in vascular smooth muscle cells [35].

β-Adrenergic modeling

Receptors have been discovered to possess the ability to bind compounds known as a ligand to obtain chemical information contained in these compounds and convert them into a biological response [37]. β-Blocker has the potential to antagonize the toxic effect of norepinephrine at the cardiomyocyte which can promote cellular remodeling of the heart for effective hemodynamics [38]. β-Adrenergic receptor subtype acts via signaling cascade to modulate cardiac function and remodeling [39]. βAR is a member of the GPCR superfamily of a receptor which enhances the regulation of various functions and processes of the CVS via signaling pathways. βAR subgroups such as β1AR, β2AR, and β3AR are fully established with their respective functions while β4AR is still not fully confirmed with viable functions. The functions of β1AR, β2AR, and β3AR are different affinities for different ligands which enhance variable activation of each subgroup [40]. The β2-adrenergic is an important tool used to regulate function in various cells and help in the treatment of CVD [41]. The application of GPCR modeling of β-adrenergic for melanin-concentrating hormone receptors was used to predict agonist-induced changes in β2AR binding pockets. The ligand binding initiates a significant variation of the protein backbone in several receptor conformations via elastic network normal mode analysis (EN-NMA) methods. The backbone conformations generated with EN-NMA can shift from the original homology occurred in cytoplasmic parts of the GPCR bundle and the ligand-binding region [42]. Moreover, the contraction of the vestibule on the extracellular side results in the formation of G protein binding pockets on the intracellular side and in turn initiates intracellular signaling. β2-adrenergic-based A2A AR model is more effective in the binding site cavity than dopamine and when applied in in silico ligand screening can stabilize ligands inside the binding pockets [43].

The effects of β-adrenergic in cardiovascular disease

Cardiac function is a complex dynamic system that strongly optimizes the circulation of blood via the vascular bed of the tissue. Neurohormonal mechanisms during HF are regarded as a progressive disease that was dominantly proceeded with the symptom as a result of activation of neurohormonal mechanisms that reduce cardiac dysfunction such as vasopressin, endothelin, nervous system, aldosterone system, and natriuretic peptide [24]. GPCRs are known for their therapeutic targets as among receptors that can respond to aminergic hormones such as epinephrine. Catecholamines including epinephrine and norepinephrine are GPCRs which have two subfamilies (α and β) and have different ligand and downstream signaling processing [44]. The production of catecholamine increases norepinephrine release in response to a stimulus [45]. The decrease in catecholamine responsiveness in elderly persons is a result of aging and the reduction of βAR sensitivity, and density in the myocardium contributed to downregulation and βARs to AC in the human heart [24].

Nevertheless, the most vital target of adrenergic stimulation is the heart and its activation causes a tremendous increase in heart rate (chronotropic), relaxation (lusitropy), and contractility (inotropy) [22]. The βAR signaling pathway is a key factor during the progression of HF between the sympathetic nervous system (SNS) and the cardiovascular system. However, when there is an improper function, the βAR signaling will result in a reduction of the β1AR level by 50%. These changes will significantly bring about the decline in βAR signaling and sustained elevation of catecholamine will emerge [9]. When β-adrenergic is overstimulated into catecholamine in the backbone, it causes CVD, stroke, HF, and cardiac hypertrophy. The prolonged activation of βARs because of different stressors induces myocardial damage such as necrosis/apoptosis, fibrosis, and cardiac hypertrophy.

Cardiac hypertrophy is the leading cause of HF [35]. The fibrosis is a major factor in heart disease due to several structural changes which occur following pathological stimuli to the cardiovascular system. The structural changes may result in the contraction of the myocardium whereas the excessive accumulation of fibrillar collagen by fibrosis is a result of myocyte death, hypertrophy, and stimulation through the various numbers of hormones. The fibroblasts are activated to form myofibroblasts and produce excess collagen called TGF-β2 and angiotensin II (Ang II). The TGF-β2 and Ang II in the process act in the synergistic pathways to interfere with the normal structure and function of the myocardium region [46]. Irrespective of the fact that GPCR can activate a pathway that is capable of elevating Ca2+ in the intracellular, the Ca2+ mobilization helps in β2-adrenergic receptor-mediated resistance in response [47]. Prolonged βAR stimulation also increase the phosphorylation of extracellular signal-regulated kinase (ERK). This increases the c-fos and c-myc in the cerebral arteries, and c-fos expression equally increases phosphorylation of ERK in the heart [35]. β-Adrenergic signaling has various pathways when crosstalk with other signaling pathways can activate both cardiostimulatory (Gs) and cardioinhibitory (Gi) pathways in order to regulate gene transcription and apoptosis or hypertrophy as shown in Fig. 1 [48]. The Gi-biased β1AR signaling can effectively protect the cardiomyocytes against induced apoptosis, and inhibition of Gi signaling may hinder cardiac response to certain diseases like ischemia and myocardial infarction (MI) [49].

Fig. 1
figure 1

A diagram describing the effects of β-adrenergic in cardiovascular disease

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GRK2 can modulate signaling because of physiological function via regulation of myocardium insulin signaling and can increase the level of GPRK2 in cardiomyocytes that lead to cell death following acute ischemic injury. The upregulation of GRK2 in cardiomyocytes increases GRK2 which on the other hand leads after to cardiac stress [50]. β2AR signaling contributes to the failing heart while β1AR expression is downregulated [51]. The downregulation results in the removal of the active receptor from the cell surface as a mechanism for cell signaling which occurs due to the phosphorylation of serine and threonine residues on intracellular domains of a βAR by protein kinase A (PKA) which is the key enzyme for cardiac function [48].

The age-related reduction or decline in the response of β-adrenergic has an impact in lowering the contractile function indicating the reduction in βAR density [52]. However, the catecholamine response is depressed in the ischemic and failing heart due to an increase myocardial βARK1 which revealed that the desensitization of βARs could protect the heart against chronic activation [33]. βARs are stimulated by catecholamines, and they are located in almost all peripheral tissue membranes [53]. The use of βARs of antagonists can potentially block the chronic activation of the βARs by norepinephrine. Recent studies confirmed that when βARK1 is upregulated, it results in the first feedback response mechanisms for initiation of SNS activity due to the βARK1 expression in the heart. This is stimulated by βARK1exposure to catecholamine that could serve as a therapeutic target for the treatment of HF or a failing heart [33].

The production of catecholamine increases norepinephrine release in response to a stimulus. The decrease in catecholamine results in aging while the reduction of βAR sensitivity and density in the myocardium contributed to downregulation leading to a decrease in response to AC in the human heart. Adrenergic stimulation enhanced chronotropy, lusitropy, and inotropy, and β-adrenergic signaling crosstalk with other signaling pathways can activate both Gs and Gi in order to regulate gene transcription and apoptosis or hypertrophy. Prolonged βAR stimulation also increases the phosphorylation of ERK. This increases the c-fos and c-myc in the cerebral arteries, and c-fos expression equally increases phosphorylation of ERK in the heart. The myocardial contraction and relaxation are determined by the rise and fall of cytosolic Ca2+ in cardiac myocytes. When β-adrenergic is overstimulated into catecholamine, it causes HF and cardiac hypertrophy. The prolonged activation of βARs under stress induces myocardial damage such as apoptosis.

βAR signaling

GPCR ligands bind to a targeted site through the extracellular face in the center of the seven helices of hydrogen bonding or charged residue to interact with the natural ligand [23]. βARs elevate catecholamine secretion from the adrenal glands [54]. Catecholamines derived from the amino acid called tyrosine determine the response ability, and βAR signaling is controlled by the GRKs [36]. βARs mediate the catecholamine-induced activation of AC via the G protein and can bind to epinephrine with up to 30-fold of affinity than it can bind to norepinephrine. β1AR, β2AR, and β3AR are heptahelical GPCRs that mediate physiological responses to the norepinephrine and epinephrine. However, β1 and β2 are expressed in the heart and can effectively regulate cardiac function in an animal [55]. The β2-adrenergic receptor site is perfectly arranged to bind organic molecules and is primarily found in smooth muscle tissue [44]. β3AR signaling acts as counterbalance “brake” against adrenergic overstimulation, and it maintains cardiac sympathovagal balance by reinforcing vagal tone. β3AR also possess coronary and peripheral vasodilatation and may have pleiotropic on the cardiac system that may prevent arteriosclerosis [56]. β2AR was the first GPCR to be cloned, and it is the most studied GPCR due to its signaling and regulation potentials and is called prototypical GPCR [57]. The stimulation of βARs produces a viable effect through the activation of G protein [58]. The β1AR and β2AR are capable of coupling to Gs which helps signal pathways since β2AR can be coupled to the inhibitory G (Gi) protein for a CAMP response [59]. In CAMP-dependent β2AR signaling, AC mediates the hydrolysis of ATP into CAMP that can activate the protein kinase known as PKA which in turn phosphorylates various intracellular substrate for effective function [57]. While β1AR stimulation by catecholamines will push for dissociation of the stimulatory G protein and alpha subunit (Gαs) from Gβγ, Gαs is responsible for the stimulation of AC yielding CAMP. Gβγ activates downstream effectors present in cardiac signaling regulation. The stimulation of β3AR has an important effect in β1AR, and β2AR stimulation through Gαs activation is thereby increasing the generation of CAMP and the activation of the PKA as shown in Fig. 2 [60, 61]. The dysfunction of the AC system is favored when the Gi protein is abnormal, and AC revealed that decentralization and uncoupling are induced, increasing GRK level. Furthermore, an increase in GRK2 in the heart elevates the development of the conspicuous failing heart [62]. Once adrenergic signaling is altered, it will activate a dilatation and decreased contractility [63] which remains an important expectation of HF and helps in downregulation and cardiotoxic signaling [64].

Fig. 2
figure 2

The diagram of βAR signaling

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β1AR signaling is necessary for both normal and disease heart function, due to dysregulation of an injured or stressed myocardium which is the core value of HF. βAR dysregulation results in upregulation and as such causes the loss of βAR responsiveness which prevails via both chronic receptor desensitization and downregulation and usually takes place due to SNS activity. GRKs phosphorylate activated receptors and initiate desensitization in order to control overstimulation [50]. The β3AR are mainly found in the myocardium and endothelium, which played a major role in CVD via modulating cardiac function and angiogenesis. β3AR possess multiple roles including vasodilation, metabolism, and relaxation to cardiac contractility, contributing to the potential therapeutic methods in heart disease. As a result, β3AR are coupled with Gαi which may be responsible for the prevention of overactivation of β1AR and β2AR [61]. It was reported that a specific adrenergic receptor mediates several catecholamine responses in energy metabolism [65]. β1 and β2 are homologous receptors which can activate the G protein, enhancing stimulatory effect for adenylyl cyclase (GS) via signaling as a result of β1AR and β2AR for biological effects. The β1AR can stimulate the heart rate and strengthen myocyte contraction while β2AR chronotropic and chronic stimulation of β1AR produces myocyte hypertrophy and apoptosis, and β2AR promotes cell survival [66, 67]. There are differences in their signaling pathways and cellular responses of types of βARs [9]. The differences in β1 and β2 receptor show that the β2 receptor has potential to couple together with Gs and Gi while β1 receptor couples only Gs and Gi enhanced by PKA-mediated β2 receptor phosphorylation [68]. For example, it is readily stimulated by β1AR than β2AR signaling [66]. The selective stimulation of β1 and β2 of AC with downregulation of β1 and β2, respectively, was a result that the β2 receptor was partially uncoupled from the previous events in the β2AR pathway [69].

The stimulation of βARs activates G protein whereas β1AR and β2AR are capable of coupling to Gs to Gi for a CAMP response. During β2AR signaling, AC mediates the hydrolysis of ATP into CAMP and then activates PKA which in turn phosphorylates various intracellular substrates for effective function. Therefore, β1AR stimulation by catecholamines will form Gαs from Gβγ and Gαs that are responsible for the stimulation of AC yielding CAMP. Gβγ activates downstream effectors present in cardiac signaling regulation. The stimulation of β3AR through Gαs activation also increases CAMP and the activation of the PKA. The dysfunction of the AC is favored when the Gi protein is abnormal, and AC increases GRK level. β1 and β2 can activate the G stimulatory (GS) protein effect for AC via signaling through β1AR and β2AR for biological effects. The β1AR can stimulate the heart rate and strengthen myocyte contraction while β2AR chronotropic and chronic stimulation of β1AR produces myocyte hypertrophy and apoptosis while β2AR also promotes cell survival. The β3AR modulate cardiac function and angiogenesis and enhance cardiac contractility, and as a result, β3AR are coupled with Gαi which could prevent overactivation of β1AR and β2AR.

β-Adrenergic signaling in cardiovascular diseases

β1AR and β2AR are expressed and distributed at the cell surface to the detached region which enhances effective signaling to Gαi [38]. All βARs (β1AR, β2AR, and β3AR) are expressed in cardiomyocytes [70]. The G protein is a heterotrimer of α, β, and γ subunits of Gα, Gβ, and Gγ, respectively, and it is inactive when binding to guanosine diphosphate (GDP) but most active while binding to guanosine triphosphate (GTP). The βAR signaling and HF progression resulted due to Gβγ-mediated signaling via desensitizing kinases called GRK2 and phosphoinositide 3-kinase (PI3K) [71, 72]. GRK2 is protective for the cell through incrementing ATP production and promoting mitogenesis [73], and GRK regulates adrenergic responses via a mechanism independent from G protein [24]. Once β2-adrenergic is coupled to downstream excitatory Gαs protein, it will activate AC yielding CAMP, producing inotropic and chronotropic responses that result in cardiac injury and [1]; at the molecular level, the process is derived by receptor phosphorylation via GRKs [29]. This will cause CAMP-mediated PKA activations to Ca2+ mediating cardiac contraction in order to increase the cardiac output [31] and causes ventricular wall motion [70] by activating cardiomyocyte βARs [59].

Therefore, upon stimulation of cardiomyocytes, βAR will bind to the stimulatory G (Gs) protein and alpha subunit (Gαs) which then activate adenylyl cyclase [9]. βAR stimulation elevates cardiac contractility, and if the βAR stimulation persists, toxicity that will affect cardiomyocytes which causes maladaptive cardiac remodeling and development of HF is enhanced. In this process, GRK helps to restrain catecholamine-mediated adrenergic signaling via receptor decentralization [74]. The aging in cardiac βAR response is because of the downregulation of β1AR, and a decreased sensitivity of βARs by isoproterenol results in conformational changes in the catecholamine-stimulated AC activity in the cardiovascular system [24]. Additionally, adenylyl cyclase as a transmembrane protein possesses two hydrophobic and two cytoplasmic domains that can convert ATP to CAMP once stimulated with βARs [75]. The cyclic nucleotide phosphodiesterases (PDEs) are responsible for catalyzing the hydrolysis of CAMP and CGMP via regulating the intracellular concentrations of the cyclic nucleotide. Phosphodiesterases are significantly upregulated in HF, which is an indelicate β-adrenergic response as a result of hydrolysis of CAMP in cardiomyocytes [2]. Then, the upregulation of GRK2 and resultant βAR desensitization are effective in the heart, but once there is a sustained elevation, it will significantly affect maladaptive cardiac remodeling and heart failure. In the failing heart, adrenergic overdriving proceeds early in the progression to HF; this shows that there are increased catecholamine levels before heart failure. The overexpression of GRK2 initiates Gi-biased signaling that neutralizes cardiac contractile response to βAR stimulation of a pertussis toxin (PTX)–sensitive manner in GRK2 transgenic mice and cultured mouse cardiomyocytes [49].

GRK modulation in the heart

G protein receptor kinase 2 (GRK2) has the potential to modulate cardiac adrenergic signaling [74]. GRKs interact with agonist activation of GPCRs to affect receptor phosphorylation which enhances impairment of receptor signaling or desensitization [76]. The role of GRK2 in regulating cytoskeletal components is to modulate cellular migration in physiological function in the inflammatory response during cardiac disease [77]. GRK is a promising therapeutic target and can regulate adult hearts through the modulation of chronotropic, inotropic, and hypertrophic signaling of 7-transmembrane spanning neurohormone receptors, but adult HF can be caused by the downregulation and desensitization of βARs [78]. GRK modulation processes are an essential characteristic that is responsible for alleviating cardiovascular dysfunction in cell culture and animal models, and GRK modulation can effectively improve human health [79]. The composite channel of control of GRK2 stability explains that the tight modulation plays a pragmatic role in GPCR signaling [80]. SNS is maladaptively activated because of the sustained reduction in cardiac output, and this increases secretion and reduces cardiac catecholamine reuptake [73]. The decrease in cardiac output by SNS response is a result of GPCR activity in different types of cell and tissue beyond the heart. When SNS is activated, there is a remarkable increase in the heart rate and contractility via catecholaminergic stimulation of cardiac βARs, and in the human myocardium, the β1 and β2 subgroups induce a positive chronotropic and inotropic adrenergic effects via Gs coupling [79]. Once β2AR are stimulated, they will produce effects called inotropic, lusitropic, chronotropic, and dromotropic which are capable of activating both Gs proteins, and this will cause β2AR to switch its signaling from Gs to Gi proteins when phosphorylated by PKA [36, 67]. Therefore, the stimulation of βAR pathway in the heart activates Gs protein, and this increases CAMP, PKA-dependent phosphorylation, and modulation that help in myocardial contractility including l-type Ca2+ channels, troponin, and ATPase inhibitory protein [51]. The CAMP is phosphorylation-dependent leading to the enhancement of active Ca2+ transport. The active Ca2+ channels are mediated by the sarcoplasmic reticulum (SR) via ATPase enzymes which act as an energy transducer and translocator of Ca2+ ion, tightly coupled with ATP hydrolysis through the formation and decomposition of an acyl-phosphorylated phosphoenzyme which is the cytosolic enzymes found in the cardiac muscle [56, 81]. In this process, the βAR stimulation activates GRK2 which is the necessary mechanism of self-regulation of adrenergic stimulation [51]. An increase in GRKs amplifies the HF pathogenesis by the desensitization of βARs, and this lead to the losses of contractile reserve [82]. GRK activation in the heart provides targets for effective GRK modulation in human therapy, and there are several levels of sequence in the tissue distribution like GRK2 and GRK3 for the regulation of endothelin, thrombin, and α1-adrenergic receptor (α1 AR) in the human heart. GPCR signaling is firmly controlled by cytosolic GRKs and can translocate to or target agonist-bound GPCRs, which initiate and phosphorylate the receptor [62, 77]. GRK2 is a cell death kinase in the heart, and its targets promote ischemic injury whereas their inhibition by the peptide inhibitor called βARKct contains the carboxyl-terminal domain of bovine GRK2 for cardioprotection found in Fig. 3 [83].

Fig. 3
figure 3

GRK modulation in the heart

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GRK2 has the potential to modulate cardiac adrenergic signaling. When SNS is activated, there is a remarkable increase in the heart rate and contractility via catecholaminergic stimulation of cardiac βARs and the human myocardium. β2AR activates both Gs proteins causing β2AR to switch its signaling from Gs to Gi proteins when phosphorylated by PKA which increases CAMP. The CAMP initiates active Ca2+ transport by ATPase enzymes tightly coupled with ATP. An increase in GRKs amplifies the HF/cell death which promotes ischemic injury whereas βARKct undergoes inhibition leading to the prevention of myocardial damage and heart preservation.

βAR agonist

Agonists help to determine different maximal responses through their intrinsic activity that can produce full agonists through the intrinsic activity value, and fraction of agonists may completely stimulate partial agonists [84]. Fluorescence spectroscopy studies suggested that β2AR are the sequential binding model of agonists, the partial agonist and dopamine have rapid binding, and a full agonist, noradrenaline, possesses biphasic binding kinetics [85]. β1- and β2-adrenergic receptors and the studies of the structural nature of receptor activation are found not only in rhodopsin but also in agonist-bound structures of β1- and β2-adrenergic receptors. βAR downregulation or desensitization mechanism contributes to the heart-related reduction in βAR response to agonists [52]. Agonist bounds to a receptor and stabilizes [23]. GPCRs are mainly modulated by the diverse spectrum of drugs ranging from full agonists to the partial agonists, antagonists, and inverse agonists [86]. It merely showed that when ligands bind to both serines, they would dominantly act as agonists. When ligands do not bind to both serines, they are termed as antagonists [87]. The crystal structure of β2AR has detail information on classical GPCR drug target, and it belongs to rhodopsin-like GPCR [88]. The 3D structure of β2AR helps to predict specific binding sites of the agonists and antagonists to β2AR [87]. Then, an agonist binds to βAR; it will initiate conformation changes that provide receptor coupling to Gsα subtype of heterotrimeric G protein which is the AC stimulatory G protein for activation of CAMP in the cells found in Fig. 4 [31]. Gi-biased β2AR signaling is agonist stimulation-dependent, and β2AR stimulation with zinterol leads to a full contractile response. β2AR phosphorylation by PKA mediates coupling to Gs and Gi, and β2AR physiological signaling through GRK-mediated phosphorylation involves the regulation of β2AR couple to Gi signaling in the heart [49]. β2AR possess a strong affinity for the agonist isoprenaline which is more efficient when coupled to Gs [11]. βARs are agonist-promoted decentralization and downregulation which decrease regulatory effector response to activate agonist stimulation initiated by the receptor phosphorylation known as GRKs [89].

Fig. 4
figure 4

The diagram which explains that when an agonist binds to βAR, it will initiate conformational changes that provide receptor coupling to Gαs subtype of heterotrimeric G protein which is the AC stimulatory G protein catalyzed by ATP into CAMP in the cells. β2AR phosphorylation by PKA mediates coupling to Gs and Gi, and β2AR physiological signaling through GRK-mediated phosphorylation involves the regulation of β2AR couple to Gi signaling in the heart. βAR agonist-promoted decentralization and downregulation which decrease regulatory effector response to activate agonist stimulation initiated by GRKs that may lead to an increase in basal activities and contractile response through signaling pathways

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The structure of β2AR consists of several ligands; there are atomic binding modes of inverse agonists and antagonists while the agonists activate the signaling pathways and increase basal activities [88]. The activation of the β2AR by catecholamine agonists and ligand binding provides that agonists activate GPCRs via a conformation intermediate [90]. The different agonist-binding sites using salbutamol, epinephrine, and isoprenaline bind in a conformation, which allows them to form a strong hydrogen-bonding network with all three of the conserved TM5 serines. β2 agonists exhibit cross-reactivity with the other ARs which causes side effects and increased heart rate and blood pressure [87]. The activation and internalization of GPCRs have an impact on normal cellular physiology and alterations in heart failure. Overexpression of cofilin mutant can alter the level of β2AR phosphorylation following agonist stimulation which enhances internalization during isoprenaline stimulation [91].

Heart failure therapy

Heart failure is a common CVD with poor prognosis which develops when the heart is not capable of pumping blood and maintaining tissue perfusion [92]. Drugs capable of interacting with GPCRs are regulated via the activation status of heterotrimeric G protein [93]. Beta-blocker is regarded as a cornerstone of HF treatment which has shown a tremendous 10 to 40% reduction in mortality rate and hospitalization in 1 year [94, 95]. β-Blockers positively reduce the mortality in patients with systolic dysfunction and chronic HF [96] and are classified into three categories: sotalol, propranolol, nadolol, and timolol are the first category and referred to as a nonselective agent. β1 and β2 blocking receptors have an impact in influencing the heart rate, conduction, and contractility whereas the blocking of β2-receptors causes smooth muscle contraction. The second category is known as cardioselective (bisoprolol, celiprolol, atenolol, and metoprolol), and they are in low dose but can block receptors in higher doses. The third category possesses vasodilatory features and is either selective or nonselective (nebivolol and carvedilol), respectively, [95]. β1-receptor blocker has advance effects in the treatment of human heart failure [97].

Furthermore, βAR blockade served as standard therapy for cardiac failure [98]. β2AR blocker serves as therapy, and when adrenergic signaling is altered, it will activate a dilatation and decreased contractility [63]. Irrespective of angiotensin-converting enzyme (ACE) inhibition, there is possible hindrance showing that either the syndrome itself or ACE inhibition probably upregulates the alternative pathway which is useful in chronic HF with an inhibitor possibly possessing long-term restriction of all plasma levels and can retrogress in the left ventricular function [99]. The preventive treatment is using pharmacological therapy with beta-blockers, ACE inhibitors for the prevention of recurrent MI, and intensive monitoring to delay disease progression [28]. In animal models, β-blockers blunt apoptosis and cardiac remodeling associated failure, inhibit β1-adrenergic receptor internationalization, and can prevent PKA-dependent Ca2+ leak from the sarcoplasmic reticulum. β1-receptor blocker and ACE inhibitors can be combined consistently to improve HF symptoms. When ACE inhibitors are applied, they could reduce cardiac hypertrophic remodeling and fibrosis [97]. Beta-blockers are adequately protected from chronically increased catecholamines, leading to upregulation of β-receptors, and its exposure induces downregulation and desensitization of β-receptors where inotropy provides longer term left ventricular systolic dysfunction. The use of β-blockers is associated with significant survival in a patient with HF.

There is a concerning caution by the American Heart Association (AHA) before the regulation of HF advocate when using β-blockers in patients with symptomatic reactive airway diseases. The outcome of β-blockers is possibly attenuated by beta-agonists [100, 101]. It also recommends that the use of β-blockade in all patients with chronic HF can reduce systolic function without contradicting to β-blockers, and the β-blockers shall not undergo conversion during hospitalization for worsening heart failure [102]. Before MI and in patients with HF, treating the patients with blockers prevents reinfarction, hospitalization for HF, and premature death [103]. The Nobel Prize honor Sir James Black has shown that the advert effect of adrenergic stimulation via blocking the cardiac β-receptors will cause inhibitory effects on the sinus node (chronotropic effect), atrioventricular node (dromotropic effect), and myocardial contractility (inotropic effect) [95]. β-Blockers are convinced to reduce the risk of stroke drastically [104].

Conclusions

The βAR signaling pathway determines the progression of HF between the SNS and the CVS through the regulatory function in various cells. Heart failure is still a public health problem in the USA. When there is stimulation of cardiomyocytes, βAR will bind to the Gs protein and Gα subunit of the Gαs which then activate adenylyl cyclase. The cell death in cardiac βAR response via downregulation of β1AR and decrease in sensitivity of βARs affect conformational changes in the catecholamine-stimulated AC activity in the cardiovascular systems. In this review, we described that once there is a change in adrenergic signaling, it will activate a dilatation and decreased contractility. It was also established that when adrenergic signaling is altered, β2AR blocker will enable a dilatation and reduced contractility.