2012 Group 7 Project

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G-protein coupled receptors: Beta-adrenergic receptors with a focus on Beta1-adrenoceptors


G-protein coupled receptors (GPCRs) are a large family of trans-membrane proteins. They are located in all organisms and are the target molecule for over 50% of the pharmacological substances at present. At lot is known about these receptors. However, due to the enormous diversity of GPCRs this project will discuss the Beta Adrenergic Receptors, specifically focusing on the Beta-1 subtype. These receptors are vital in maintaining human physiological conditions, particularly cardiovascular physiology.

This project will take you through the a basic overview firstly, followed by the history of this family of receptors. The receptor structure, function and abnormalities will be then be explored. As there is still much to be known about this receptor, a current research section at the end of the page will highlight some research which is being undertaken at present.

Overview of Receptor Interactions

GPCR process - student image

G-protein coupled receptors (GPCRs)[1], guanine nucleotide proteins, belong to the biggest and most diverse protein family of transmembrane receptors, which appear in eukaryotes.[2]

It is involved in physiological effects such as signal transfer[3]: molecules from outside the cell cause in combination with GCPR an immediate reaction inside the cell.[4] Signal molecules represent an enormous variation inclusive of hormones, neurotransmitters, and local mediators.[5] These then bind to a receptor on the surface of the protein.[2] A receptor is a protein that has the ability to bind certain particles due to its special binding side and starts a process of signal transfer inside of the cell.[6] [7]

GCPRs play a big role in inflammation processes, cell movement, transport of particles through the membrane or cell growth and differentiation.[2] Moreover it handles with attractions and completes the final structure of hormones and therefore their later impact.[4] In the following you will find detailed information about the pathway and possibly diseases that can occur when the process is not working correctly.[8]

There are two different signal pathways in that GCPRs are involved: cAMP signal pathway and phosphatidylinositol signal pathway. Nevertheless the main process can be described in four steps as it is visualized in the picture:

1. GPCRs have great similarities in their structure. The polypeptide chain which builds them up mainly coils up back and forth the membrane seven times. The associated inactive G-protein is a trimer, which is built up of three protein subunits α and βγ. In the unstimulated state the α-subunit has a GDP-bound.

2. The G-protein coupled receptor is brought into action when there is a signal outside the cell arriving and binding to the receptor of the inactive GPCR. Signals can be in form of ligands or signal mediators. The key-lock principle reaction causes a conformational change of the GPCR which in return makes it act as a guanine nucleotide exchange factor. Immediately the connected G-protein is mechanically activated by exchanging its bound GDP for a GTP.

3. For reason of the activation, the α-subunit monomer and GTP-bound can separate from β- and γ-dimer. These then affect intracellular signaling transduction pathways and target functional proteins. The way of reaction is according to the type of α-subunit since there is a variety.

4. When the signal molecule which was linked to the receptor leaves, everything changes back into the inactive state. The α-subunit changes its bound and the GPCR transforms back into its old confirmation. The α-subunit has the ability to hydrolyze GTP to GDP. Thus allows the reconnection of the three subunits to an inactive G-protein, which awaits a new activation through the associated GPCR. Generally, the time of separation of the subunits is very short depending on how fast the α-subunit hydrolyzes its bound GTP. [9]


Adrenergic systems play an important role in system-regulation. They are responsible for diseases when they do not work properly. As shown in the table, there are different G-protein coupled receptors and different subunit-types. Depending on the combination of those, the way of reaction is different.

There are three main classes, which can be differed with the help of three approaches. They are categorized depending on their sequence similarities (1), receptor pharmacology (2) or their signal mechanisms (3). Within these defined classes there are further subdivisions.

To point out some of the mentioned receptors from the table: Αlpha-1 adrenoceptors are most likely found in arterial smooth muscles and responsible for vasoconstriction stimulation. Beta-1 adrenoceptors occur in the heart and are involved in heart stimulation processes and its discharge. Beta-2 adrenoceptors appear in skeletal muscles and they stimulate the vasodilatations. They are implicated in asthma-affections.[10]

History of pathway

1854-1915 The idea that drugs bind to specific sites or receptors on cell surfaces - Paul Ehrlich [11]. Please note that the original article is in German and not available on the internet, hence the reference of a review article is provided.
1852-1925 Use of the term ‘receptive substance’ - John Langley, further developed by Sir Henry Dale [11]. Please note that the original article is not available on the internet, hence the reference of a review article is provided.
1949, 1956 Development of concepts of affinity and efficacy. Development of the quantitative methods by which the properties of agonists, partial agonists and antagonists can be evaluated from the measurement of functional responses in isolated tissues - Arunlakshana and Schild [12], Stephenson [13]
1962 The discovery of cyclic AMP as the factor mediating the effect of epinephrine on glycogenolysis and of cAMP mediating the effects of other hormones - Sutherland and Rall.[14] [15] [16] [17]
1972 This resulted in the award of the Nobel Prize for Physiology or Medicine in 1971 to Sutherland and Rall.[18]
Early 1970s Growing realisation that the receptor structures responsible for stimulating cyclic AMP formation involved separate proteins for agonist recognition (receptor), cyclic AMP synthesis (adenylyl cyclase) and the transduction of information from the receptor to adenylyl cylase (heterotrimeric G-protein). [11]
1994 Gilman and Rodbell shared the Nobel Prize in Physiology or Medicine in 1994. This was "for their discovery of G-proteins and the role of these proteins in signal transduction in cells". The Nobel Prize in Physiology or Medicine 1994. Nobelprize.org. 8 May 2012
1997 Development of the concept of GPCRs and the vital role of G-proteins in signal transduction processes - Research teams of Gilman [19] and Rodbell [20]
2000 Structure of Rhodopsin was determined - Palczewski et al. research teams [21] Rhodopsin structure discovery
2003 Fluorescence resonance energy transfer (FRET)-based studies suggest that, at least for certain G-proteins (particularly Gi type), a conformational rearrangement might occur rather than separation of the alpha subunit and beta & gamma subunit [22]. This showed that models that may be accepted for many decades are not completely accurate depictions of the true molecular events.
2003 Analysis of the sequenced human genome (HUGO), led to the identification of over 800 GPCR genes [23]
2007 Unraveling of the first structure of a G-protein coupled receptor which was activated by a ligand[24]. As a result,also the structure of a β2-adrenergic receptor structure was determined- Rasmussen et al. research teams [25]
2008 Approximately 180 membrane protein structures are known[24], including the β1-adrenergic receptor structure - Warne et al. research teams[26] Structure of a beta1-adrenergic G-protein-coupled receptor

Gene description of Adrenergic receptors

Adrenergic receptors can be classified into different subtypes, namely alpha and beta.

This group project places a specific focus on beta-adrenergic receptors, which can be further classified into different subtypes, each of them being coded for by a different gene.

The genes, ADRB1, ADRB2 and ADRB3 each code for the expression of the Beta adrenoceptors subtypes below. It has been long established that DNA mutations and genetic defects lead to disease and illness. Studies have been conducted into the rate of evolution of these genes, in order to infer whether environmental changes act as selective forces driving evolution, subsequently leading to changes in these receptors[27] .

Beta 1

The gene coding for Beta-1 adrenergic receptors is located on chromosome 10, 10q24-q26.

The gene is protein coding for 477 amino acids. Beta-1 adrenoceptor gene

Defects with ADRB1 are the focus of this project (include a variety of cardiovascular disorders) and are discussed in Abnormal section.

Beta 2

The gene coding for Beta-2 adrenergic receptors is located on chromosome 5, 5q31-q32.

The gene is protein coding for 413 amino acids. Beta-2 adrenoceptor gene

Defects ADRB2 are linked with asthma (MIM 600807).

Beta 3

The gene coding for Beta-3 adrenergic receptors is located on chromosome 8, 8p12.

The gene is protein coding for 408 amino acids. Beta-3 adrenoceptor gene

Defects in ADRB3 are associated with insulin resistance and obesity (MIM 601665).

Receptor Agonists

MCB - Section - 20.3 - G Protein –Coupled Receptors and Their Effectors

The endogenous agonist Adrenaline
The endogenous agonist Noradrenaline

Subtype Natural Agonist Synthetic Agonist Non-specific Beta-blocker examples Specific Beta-blocker examples
Beta 1

Adrenaline (A), Noradrenaline (NA)

Isoproterenol (ISO)

Propranolol, Timolol, Nadolol

Cardioselective blockers - Metoprolol, Atenolol, Bisoprolol, Betaxolol

Beta 2



Propranolol, Timolol, Nadolol

Butaxamine, ICI-118,551

Beta 3



Propranolol, Timolol, Nadolol

SR 59230A

Table information taken from Rang & Dale's Pharmacology. [28]

Receptor Structure

In order to have a valid and precise understanding of the mechanisms involved in activation and signal transduction pathways, it is a vital requirement that the structure of each GPCR be identified. Due to new technological advances more and more is beginning to be discovered about different structures across families and within subtypes of families.

This is a depiction of a standard GPCR. It shows the seven hydrophobic domains (different colours)which can be seen to spam the membrane (yellow)

General Classification

One key step in categorising the GPCR's came after the human genome was determined. Analysis of the human genome found that the GPCR were the largest group of membrane proteins, with approximately 800 unique types.

There are considered to be 5 families [23]:

- Rhodopsin, contains 701 members (Beta adrenergic GPCR fit into this category)

- Adhesion, 24 members

-Taste, 24 members

- Glutamate, 15 members

- Secretin, 15 members.

- There is a large portion of 'orphan' GPCR which don't fit into a specific family.

General components

MBoC - Figure 15-26 , this link provides an illustration of a simple GPCR.

  • The defining aspect of GPCR which is the basis of all receptors is that all contain seven membrane-spanning hydrophobic domains (alpha helices). Often GPCR are termed 7TM receptors or serpentine receptors due to this property.
  • The receptor is composed of a single polypeptide chain
  • Connecting the 7TM segments are 3 intracellular loops (labelled IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3).
  • It is also common that there is an extracellular amino terminus (N-terminus) segment and an intracellular carboxyl terminus (C-terminus).
  • The structure of the N- and C- segments may regulated other functions besides basic agonist binding. The C-terminus usually contains serine (Ser) or threonine (Thr) residues that can be phosphorylated to increase the affinity and accelerate binding of regulatory proteins called β-arrestins [29]

This is a more detailed illustration of a standard GPCR shown simply in 2 dimension

Even though the three Beta adrenergic receptors are considered GPCR, they are structurally unique. The amino acid sequence between Beta-1, and Beta-2 Adrenoceptors differs by approximately 50 amino acid differences. These differences are even larger when compared to the alpha adrenoceptors[30].

The most variation in the GPCR comes from structural variations of: -A-terminus (greatest variation) -C-terminus -TM loop 5 -TM loop 6 The tertiary structure of this protein is a barrel shaped, this can be seen by observing the depictions of the receptors.

Another factor that causes structural variation is the range of agonist which bind to the receptor. There are a variety of ligands that bind to activate different types of GPCR's. These can be subatomic particles (photons of light-rhodopsins), ions (Ca2+), proteins and peptides, hormones, neurotransmitters. The agonist needs to interact with the active binding site on the GPCR, therefore structure will vary based on this factor. Not all GPCR express the binding site on the extracellular domain (N-terminus), this may be the case for proteins or peptide agonists, but consider Ca2+ as an agonist, such as small ion could cross the lipid bilayer and the binding site may well be within or across the TM domains. [31]

For an agonist binds, an inactive receptor state is present, this can be depicted at MBoC - Figure 15-27 . After an agonist binds this causes a conformational shape change in the receptor itself. This allows the activation of the intracellular G-proteins. This can is shown in MBoC - Figure 15-28

G-Protein Structure

In order to obtain a specific visual of certain GPCR, certain high resolution techniques are required (for example crystal screening, crystallography, fluorescence spectroscopy) . Obstacles are continually present, these include protein production, purification (without damage to GPCR), protein stability. [31]

Beta-1-Adrenoceptor Structure

  1. Specific details about the structure of this receptor can be accessed from GPCRDB[31], information on Beta-1 .
  2. Another database for information regarding, Beta-1 Adrenergic Receptors from Drug Bank[32].

Pathway and Normal function

Stimulatory pathway

MCB - Figure 20-16- Activation of adenylyl cyclase following binding of an appropriate hormone (e.g., epinephrine, glucagon) to a Gs protein – coupled receptor a link to an illustration of the activation of adenylate cyclase. A movie of extracellular signalling is also present.

β-adrenergic receptors are activated by specific agonist compouds. These include direct agonists such as dobutamine (specific for β-1 receptors) and endogenous catecholamines like adrenaline and noradrenaline. As depicted in the illustration, we will consider the binding of an endogenous catecholamine which leads to initiation of the stimulatory pathway.

  • The review by Cabrera-Vera et al. (2003) explains that the first step in signalling is accomplished by activation of the heterotrimeric G protein Gs, promoting dissociation of its α and βɣ subunits [33].
  • Next, the α-subunit binds to the membrane-bound effector protein adenylate cyclase, stimulating the synthesis of cyclic AMP from ATP[33].
  • As a second messenger, cyclic AMP causes the dissociation of regulatory and catalytic subunits of protein kinase A, as reviewed by Taylor et al. (1988)[34].
  • The catalytic subunits of protein kinase A are now able to phosphorylate numerous substrate proteins including ion channels, myofilament proteins, and metabolic enzymes[33]. Protein kinase A-dependent phosphorylation mediates many of the physiologic consequences of β-adrenergic receptor signaling.
  • Phosphodiesterases eventually degrade the cyclic AMP and protein phosphatases dephosphorylate protein kinase A substrates, consequently terminating and reversing the previous events[35] .

As mentioned by Saucerman and McCulloch (2006) in their review article, β-adrenergic receptor signaling has been thought to have four main functional roles in the heart: to increase the heart beating rate, contractility, relaxation rate, and to modulate metabolism as required by those increased energetic demands. Cardiac myocytes express two main β-adrenergic receptor isoforms, β1-adrenoceptors and β2-adrenoceptors (75%:25%)[36].

β-adrenergic receptor pathway - student image

  • Phosphorylation of the Ryanodine receptor 2 on the sarcoplasmic reticulum due to the catalytic subunits of protein kinase A increases the opening probability and leads to an elevated Ca2+ flux to cytoplasm[37].
  • Elevated Ca2+ in cardiac muscles causes an increase in heart rate.
  • Increased contractility is primarily due to protein kinase A-mediated phosphorylation of the L-type calcium channel located in the cell membrane, and phospholamban located in the cytosol [36].
  • β-adrenergic receptor signaling increases the Ca2+ current, bringing additional calcium into myocytes for larger contractions.
  • 2,3-Phosphorylation of phospholamban releases its tonic inhibition of the Ca2+ pump located in the membrane of the sarcoplasmic reticulum, sequestering more Ca2+ into the sarcoplasmic reticulum for larger subsequent contractions [36].
  • Furthermore, the increase in Ca2+ flux from cytosol to sarcoplasmic reticulum accelerates relaxation of the myofilaments.
  • To keep up with the energy demands, protein kinase A also activates phosphorylase kinase, a metabolic enzyme that increases rates of glycogen breakdown. Additional glucose and increased cellular ATP are provided to retain the rate and force of cardiac contractility [36].

Inhibitory pathway

Inhibition of the pathway mentioned above can occur due to binding of Beta-adrenergic receptor antagonists, more commonly known as Beta blockers to the receptors. These compounds block in particular the action of the endogenous catecholamines adrenaline and noradrenaline, as reviewed by Frishman and Saunders (2011)[38]. Levels of cAMP will decrease as a result and further pathway signalling has been prevented. They are mainly used to treat hypertension as their effects are to reduce excitement caused by the sympathetic nervous system [38]. However, they have minimal effects when patients are at rest.

Experimental findings have indicated that attenuation of the production of cAMP is insufficient as the only signal for educing the many effects observed. Despite additional biochemical and electrophysiological changes which must occur, we will solely focus on the role of beta-adrenergic receptors in this process [39].

Beta-2 adrenoceptors have been linked to the heterotrimeric G protein Gi. As with the Gs protein, the Gi protein is made up of an alpha, beta and gamma subunit which can dissociate. Dissociation occurs once energy is provided by conversion of GTP to GDP. This will cause the alpha subunit to interact with adenylate cyclase [39]. Instead of causing a stimulatory effect, this mechanism causes an inhibitory effect. Less ATP is converted to cAMP, hence the separation of regulatory and catalytic subunits of protein kinase A has been prevented. As a consequence, no phosphorylation of cell signalling constituents occurs and the effects normally observed by activation of adenylate cyclase are now diminished.

Regulatory mechanisms

Regulation of the adrenergic signalling pathway can be achieved in many ways.

1) Control of cAMP levels

Signalling complexes can be formed between adrenergic receptors and cAMP-specific phosphodiesterase (PDE). The Beta2-adrenergic receptor forms a complex with both Beta-arrestin and the PDE4D5 isoform. Agonists are required to bind to the Beta2-adrenergic receptor in order to form this complex [40].

On the other hand, Beta1-adrenergic receptors form a direct signalling complex with a cAMP-specific phosphodiesterase isoform, namely PDE4D8. Furthermore, binding of agonists to the receptor will result in dissociation of the complex. Our current understanding, as reviewed by Cotecchia et al. (2012), is that this complex might allow for the control of cAMP levels in proximity of the receptor [41].

2) Regulation by Beta-arrestin

As explained in the review by Vasudevan et al. (2012)[42] and in the student-drawn illustration provided:

Pathway regulation by Beta-arrestin. Student image.

1. The receptor is phosphorylated [43]. This can be done in different ways: G-protein coupled receptor kinases cause phosphorylation of receptors that are occupied by an agonist, while phosphokinase A and phosphokinase C can phosphorylate β-adrenergic receptors despite the specific occupancy or activity status of the receptor [42].

2. β-arrestin is recruited to the phosphorylated receptor complex [42].

3. Binding of β-arrestin to the receptor complex. Once bound, the receptor can no longer interact with the G-protein and desensitization occurs. This prepares the receptor toward internalization [42].

4. Internalized β-adrenergic receptors are directed to recycling endosomes [42].

5. The receptors are either resensitized or degraded. Resensitization involves dephosphorylation of the receptor and recycling it back to the plasma membrane where it is ready for new stimulation [44]. When the receptor needs to be degraded it will be trafficked to a lysosome [42].

The homeostatic functioning of the adrenergic receptor is preserved by the mechanisms of desensitization and resensitization [42].

Please follow the links provided for more information on the role of Beta-arrestins:

G-protein coupled receptors and Beta-arrestins

MCB - Arrestins Have Two Roles in Regulating G Protein – Coupled Receptors

Abnormal Function, Diseases and Treatments


This table gives an overview of some of the serious diseases associated with Beta 1 and other beta receptors. For more information, please refer to the text below the table.

Abnormal Function Disease pathogenesis Treatment
Increased Beta 1 activity [45]

[46] [47] [48]

Tachycardia, tachyarrhythmia, Sudden Cardiac Death [45] [46] [47] [48]

B arrestin brings Epac and CaMKII to the Beta receptor C domain to activate CaMKII signalling. This increases intracellular Calcium to stimulate excessive heart contractions[45] [46] [47] [48]

Amiodarone, Metoprolol [49] [50]

Autoantibodies to Beta 1 receptor [51]

Dilated cardiomyopathy (DCM)[51]

Autoantibodies stimulates a down-regulation of Beta 1 receptors. This leads to damage to cardiomyocytes and pooling of blood in the heart, causing DCM [51]

Immunoadsorption therapy [52]

Down Regulation of Beta 1 receptors [53]

Right Heart Failure [53]

The decrease in the number of Beta 1 receptors in the right heart cause lower levels of calcium release. This stimulates weaker contractions, preventing blood to be pumped out. [53]

Epoprostenol [54]

Polymorphisms of Beta 2 receptor gene [55]

[56] [57]

Nocturnal Asthma [55] [56] [57]

Polymorphism changes arginine to glycine at position 16 of the Beta 2 receptor gene. This reduces expression of B2 receptors, leading to increased chance of bronchospasms[58] [55]

Salmeterol [56]

Chronic Beta 3 Activation [59]

Metabolic disorders leading to obesity [59]

Chronic activation of beta 3 receptors causes a decrease in Leptin and melanocortin secretion. This causes increased appetite and mood elevation. [59]

No drugs effective for obesity [59]

Increased activity of Beta 1 and Sudden Cardiac Death (SCD)

Sudden cardiac death - disease background:

Sudden cardiac death (SCD) is the unexpected death caused by cardiovascular abnormalities, within 1 hr after symptoms occur. [45] B1 receptor over activation causes ventricular tachycardia. [46] This ventricular tachycardia can degenerate into Ventricular arrhythmia and fibrillation. [46] Ventricular fibrillation (VF) is the major cause of SCD, as reviewed by Chugh.[60] As summed up in the review by Chugh, in most age groups there is higher incidence in males and the age group with the highest incidence was 75-84. .[60] Around 300000 people in the US get Sudden cardiac death annually. [47]

Receptor Malfunction and Pathogenesis of SCD:

This is a schematic of how Beta-arrestin fails to turn off the Beta 1 signalling properly and leads to activation of CamKII with subsequent increase in cytosolic calcium. This increase in calcium can cause tachyarrhythmias and heart failure.

Chronic activation of the Beta 1 adrenergic receptor in the heart may cause ventricular tachycardia and heart failure in the form of sudden cardiac death. [46] Chronic activation of Beta 1, causes G protein coupled receptor kinase (GRK) to phosphorylate the intracellular domains of Beta 1 receptor and recruit Beta-arrestin to bind. [46] Binding of Beta-arrestin prevents G protein from interacting with Beta1-receptor and causes receptor endocytosis. [46] This is the mechanism the cell employs to turn off inappropriate Ca2+ release and over contraction of cardiomyocytes. However, in patients with tachycardia, B-arrestin acts as a scaffolding protein that brings 2 proteins Epac and Ca2+/calmodulin-dependent protein kinase II (CamKII) to the Beta 1 receptor. [46] By bringing Epac to the plasma membrane where adenylatecyclase is, Epac is in close proximity to the cAMP produced by adenylatecyclase. Epac is a protein that can be activated (via phosphorylation) by cAMP. [46] Once activated, Epac starts a short signalling pathway that results in the phosphorylation and activation of CamKII. CamKII initiates downstream signalling to increase cytosolic Ca2+ via sarcoplasmic Ca2+ leaking and ryanodine receptor phosphorylation. [48] Ryanodine receptor phosphorylation allows influx of calcium from the sarcoplasmic reticulum. [48] This inappropriate Calcium release trigger tachycardias and arrhythmias that lead to sudden cardiac failure. [48] The reason why Beta 1 induced tachyarrhythmias can lead to SCD is that when a heart undergoes tachyarrhythmia, it does not contract properly. [48] This means blood is not pumped into the aorta and coronary artery, causing the heart muscle to die.

Drug to prevent Sudden Cardiac Death:

  • Amiodarone

Amiodarone is an antiarrhythmic drug used preventing Sudden cardiac death. [49] It reduces mortality from those at risk of SCD by 10-19%. [49] People at risk of SCD include those suffering from Beta 1 induced arrhythmias. [49] Amiodarone is also widely used to treat ventricular tachyarrhythmias. [49] It works by blocking both Beta 1 receptors and calcium channels in the heart. [49] By reducing the Beta 1-adrenergic signalling in cardiomyocytes, amiodarone counteracts the over-stimulation of Beta 1 receptors seen in patients with ventricular tachyarrythmias. [49] Since ventricular tachyarrhythmia is the main cause of SCD, amiodarone can prevent the onset of SCD. Amiodarone can have serious side effects. [49] Long term use can result in pulmonary fibrosis.[49]

  • Metoprolol:

This is a B1 selective antagonist which means it reduces the activity of Beta 1 but has minimal effects on beta 2 adrenergic receptors. [50] By inhibiting neural stimulation of the Beta 1 receptors, metoprolol prevents cardiac arrhythmias that may lead to SCD. [50] When taken daily over 8 weeks, metoprolol can significantly reduce the chance of sudden cardiac death compared to the placebo control group. [50]

This figure shows the differences between various forms of Cardiomyopathies. Dilated cardiomyopathy (C) is just one of the many cardiomyopathies. It shows decreased heart wall thickness and increased ventricular lumen.

Autoantibodies against Beta 1 can lead to Dilated Cardiomyopathy (DCM)

Dilated Cardiomyopathy (DCM)- disease background:

DCM is the continual dilatations and reduced contractility of the ventricles. [51] About 30-40% of cases are caused by toxic chemicals like alcohol but 60-70% of DCM is thought to be associated with production of anti-Beta 1 antibody. DCM can lead to sudden cardiac death. [51] This is because in DCM, the contractility of the left heart is impaired and dilated so it cannot pump blood out into the aorta effectively. [51]

Receptor Malfunction and Pathogenesis of DCM:

This is a self drawn diagram showing the pathogenesis of DCM

Dilated Cardiomyopathy (DCM) has been found to be caused by an antibody that targets the Beta 1 receptor. [51] In DCM, many patients produce antibodies can bind to the extracellular domains of the Beta 1 receptor and act as an agonist.[51] One such antibody is the Anti-Beta 1- ECII antibody. [51] This antibody binds to the second extracellular domain of the Beta 1 receptor and stimulates the receptor. [51] One study has shown that when mice with the human Beta 1 receptor were given this antibody, initially there was an increase in downstream Beta 1 signalling molecules such as cAMP and PKA. [51] This suggested the anti-Beta 1 antibody is acting as an agonist, over-stimulating B1 receptor. In an attempt to maintain homeostasis, the heart down-regulates B1 receptors. [51] Jahns et al, have found a 25 fold decrease in Beta 1 receptors of anti-B1 stimulated mice. Over 9 months of exposure to the anti-Beta 1 antibody, they found Left ventricular dilatations and dysfunction. [51] Whether it is the down-regulation of B1 receptors or the initial over stimulation of Beta 1 that caused the ventricular dysfunction is unknown. It is possible that after down regulation of Beta 1 receptors, the heart no no longer contracts properly and this leads to pooling of the blood in the left ventricles, causing dilations. It is also possible that Beta 1 over stimulation may cause direct damage. [51] The exact mechanism is still yet to be discovered. Nonetheless, the LV dilations and contractile dysfunction that result from Anti-Beta 1 antibodies are characteristic of DCM. [51] See flow chart for summary of pathogenesis.

Drugs to treat DCM:

  • Immunoadsorption (IA) therapy

Immunoadsorption (IA) therapy can be used for DCM. This therapy removes the auto-antibodies against Beta 1 receptor. [52] IA has been shown to increase heart function in patients suffering DCM due to anti-Beta 1 antibodies. [52] In clinical trials, Anti-IgG columns are used to reduce the amount of IgG antibodies such as anti-B1 in DCM patients. [52] Patients were found to have increased Left ventricular ejection fraction after treatment. [52]

This is a self drawn schematic of the pathgenesis of Right Heart Failure

Down regulation of Beta 1 in the heart leads to Right Heart Failure:


In the heart, activation of B1 leads to increased cytosolic Ca2+ which stimulates the force and rate of contraction of the cardiomyocytes. [53] People with Primary Pulmonary Hypertension (PPH) are susceptible to right ventricular heart failure. [53] This is because these patients have decreased expression of Beta 1 adrenergic receptors in the myocardium of their right ventricles compared to normal people. [53] Low Beta 1 leads decrease in G protein α subunits, adenylate cyclase and PKA activation. [53] These aspects lead to decreased Ca2+ influx, causing weaker and slower contractions of Cardiomyocytes. [53] Due to high pressure in the pulmonary circulation in these PPH patients, the weak contractions of their right heart cannot force the blood into the pulmonary circulation. This results in right ventricular failure.

Right heart Failure – Drugs:

  • Epoprostenol

This is a prostacyclin (PGI2) analog and it is a known vasodilator. [54] In patients with pulmonary hypertension and are susceptible to right heart failure, Epoprostenol improve the haemodynamic effects of the right heart. [54] Acute (short term) administration of Epoprostenol have been found to increase inotropy and reduce ventricular afterload of the right heart. [54] However, this drug, if given over long periods of time can increase mortality rate.[54]

Polymorphisms of Beta 2 receptor can cause Nocturnal Asthma:

A common prescribed medication used in the treatment of Asthma 9(contains Salmeterol)

Background - Nocturnal asthma:

Nocturnal asthma is essentially the worsening of asthmatic symptoms during the night. [55] It is not a separate disease from asthma but it is rather a phenotype of asthma. [55] This experienced by nearly 40% of asthma sufferers. [55] Majority of asthma-related deaths also occur during the night. [55] Symptoms of Nocturnal asthma include coughing, breathlessness, gasping and wheezing. [56] These symptoms result from bronchoconstriction or contraction of the bronchial smooth muscles. [57] Such bronchconstriction is caused by an inflammatory response in the walls of the respiratory airway. [57] Such inflammation is mediated by immune cells such as mast cells and eosinophils. [57] Since normal Beta 2 adrenergic receptor stimulation dilates the bronchial smooth muscle and prevents asthma, any mutations in the gene encoding this receptor have been linked to different asthma phenotypes and severity. [55][57]

Malfunctioning Beta 2 and nocturnal asthma pathogenesis:

So far 9 single nucleotide polymorphisms (SNPs) have been detected in the gene encoding the Beta 2 adrenergic receptor. [58] [55] These SNPs are single base changes that can lead to changes in the amino acids that make up the receptor protein. If the amino acid Arginine is changed to Glycine at position 16 of the Beta 2 receptor polypeptide, there is increased risk of getting nocturnal asthma. [58] Lee et al found that the occurrence of nocturnal asthma was 3 times higher in children with mutated Glycine16 allele compared to those with normal arginine16 allele. [58] The mutation glycine16 down regulates Beta 2 adrenergic receptors. [55] One possible reason for this down-regulation is that the Glycine16 mutation changes the degradation of Beta 2 adrenergic receptors, leading to a significant decrease in its expression. [55] Stimulation of Beta 2 receptor causes relaxation of bronchial smooth muscle and helps prevent asthma. Thus, by reducing the number of Beta 2 receptors, the Glycine16 polymorphism increases the chance of asthma. [55]

Drug Treatment

  • Salmeterol:

Salmeterol is a long-acting Beta 2 agonist that is given by inhalation to reduce symptoms of nocturnal asthma like bronchconstriction. [56] A study by Fitzpatrick et al, has found giving 50ug of salmeterol daily can reduce bronchoconstriction and increase the length of deep (stage 4) sleep as compared to a placebo in a group of nocturnal asthma sufferers. [56]

Chronic activation of Beta 3 in response to stress, can lead to Obesity


It has been found that people, especially young women, who are depressed, are more likely to be morbidly obese. [59] One study found late adolescent girls with depression, had a 2.3 times higher risk of getting obesity in their adult life. [59] This exact mechanism of this obesity has recently been associated with chronic activation of Beta 3 receptors. [59]


Chronic deficit social stress has been found to induce chronic signalling and activation of Beta 3 adrenergic receptors. [59] This study was done in mice. [59] Increased Beta 3 signalling in mice results in decreased leptin levels and decreased melanocortin signalling. [59] The decrease in leptin and melanocortin causes an increase in appetite and mood elevation. [59] At the end of this study, mice had gained weight. [59] Thus Beta 3 receptor activation provides an explanation for the association of stress or depression and weight gain.


Currently, there are no effective drugs for treating Beta 3 associated obesity.[59] The Beta 3 antagonists (such as SR59230A) have being tested. [59] These antagonists increase leptin and melanocortin levels and may prevent weight gain. However they are associated with increased stress and worsening behavioural symptoms. [59] This treatment may lead to depression and thus is not useful.[59]

Current Research

Beta 2 Adrenergic Receptor has been linked to Breast Cancer:

This is a self drawn image showing the link between hormonal treatments, beta 2 expression and breast cancer prognosis.

Beta 2 over-expression has been associated with the ‘luminal’ breast cancer phenotype. [61] If the patient is treated with hormonal drugs like Tamoxifen, the prognosis for the patient is good, during treatment. [61] However, once the hormonal treatment is withdrawn, the patients with high levels of Beta 2 expression have very poor prognosis. [61] It is possible that hormonal treatments reduce the amount of Beta 2 receptors in the breast and give better outcomes. [61] If this is so, then beta 2 blockers may be useful for treating breast cancers. [61] The exact mechanism is still unknown.

Unlocking G-protein coupled receptors:

Recently, the clinical-stage biopharmaceutical and listed company Omeros is brought into attention of media because they identified a comound, that interacts with GPCR. Through these interactions, Omeros's GPCR program was able to unlock 37 receptors.


Beta 3 receptors have been found to play a role in Cystic fibrosis (CF)

Beta 3 receptors have recently been found on the human bronchi. [62] In CF patients, their bronchial epithelial cells have up regulated beta 1 and beta 3 receptors. [62] However, beta 2 is down regulated. [62] Since Beta 3 has relatively limited distribution compared to beta 1 and 2 receptors, developing a beta 3 selective drug to treat CF may give fewer side effects. [62] This is currently under research.

Activation of beta 1 receptor can be a potential treatment for Down’s Syndrome:

Xamoterol is a beta 1 agonist. [63] When this was given to transgenic mice (displaying phenotypes of Down’s syndrome), memory and some cognitive deficits were restored in these mice. [63] The exact link between beta 1 signalling failures and Down’s syndrome is still been investigated. [63] The implication of this research means in the future Beta 1 selective agonist may be used as a treatment for the symptoms of Down’s syndrome. [63]

Glossary of terms

  • GPCR: G-protein coupled receptor
  • Alpha helices: a common folding pattern in proteins in which a linear sequence of amino acids folds into a right-handed helix stabilized by internal hydrogen bonding
  • ATP: Adenosine-5'-triphosphate: a good energy source for metabolic processes, is a multifunctional nucleoside triphosphate used in cells as a coenzyme.
  • Cardiac myocytes: a specialized muscle cell present in the heart
  • Cyclic AMP (cAMP): a nucleotide generated from ATP by adenylyl cyclase in response to stimulation of many cell-surface receptors. cAMP acts as an intracellular signaling molecule by activating cyclic-AMP-dependent kinase (protein kinase A, PKA)
  • Cytosol: the intracellular fluid found inside a cell
  • Dissociation: disuniting or separating an object into parts
  • Endogenous: coming from within/self-produced by body tissues
  • G-Protein Coupled Receptor (GPCR): a transmembrane receptor which is linked to a G-protein, allowing for signalling through second messengers.
  • Gi: inhibitory G-protein
  • Gs: stimulatory G-protein
  • Gq: a class of G-protein which activates phospholipase C-β and originates the inositol phospholipid signaling pathway
  • Heterotrimeric protein: a protein made up of 3 different subunits
  • Myofilaments: contractile protein filaments with a highly organised arrangement, making up a muscle sarcomere
  • Phosphodiesterase: an enzyme that breaks a phosphodiester bond
  • Phospholamban: a 52-amino acid integral membrane protein that regulates the Ca2+ pump in cardiac muscle and skeletal muscle cells
  • Phosphorylate: to cause (an organic compound) to take up or combine with phosphoric acid or a phosphorus-containing group
  • Protein isoform: A protein that has the same function as another protein but which is encoded by a different gene and may have small differences in its sequence
  • Sarcoplasmic reticulum: a system of membrane-bound tubules that surrounds muscle fibrils, releasing calcium ions during contraction and absorbing them during relaxation
  • Synthesis: a combination of two or more entities that together form something new
  • Tachycardia: A rapid heart rate, usually defined as greater than 100 beats per minute
  • Tachyarrhythmia: is any disturbance of the heart rhythm in which the heart rate is abnormally increased

When defining the terms in this glossary we used the online dictionary resource - MedTerms and the online dictionary resource - Medical Dictionary as resources.



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