Thebeta-1 adrenergic receptor (β1 adrenoceptor), also known asADRB1, can refer to either the protein-encoding gene (gene ADRB1) or one of the fouradrenergic receptors.[5] It is aG-protein coupled receptor associated with theGsheterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.
W.B. Cannon postulated that there were two chemical transmitters orsympathins while studying the sympathetic nervous system in 1933. These E and Isympathins were involved with excitatory and inhibitory responses. In 1948,Raymond Ahlquist published a manuscript in theAmerican Journal of Physiology establishing the idea of adrenaline having distinct actions on both alpha and beta receptors. Shortly afterward, Eli Lilly Laboratories synthesized the first beta-blocker,dichloroisoproterenol.
ADRB-1 is atransmembrane protein that belongs to the G-Protein-Coupled Receptor (GPCR) family.[6][7] GPCRs play a key role in cell signaling pathways and are primarily known for theirseven transmembrane (7TM) helices, which have a cylindrical structure and span the membrane. The 7TM domains have three intracellular and three extracellular loops that connect these domains to one another. The extracellular loops contain sites for ligand binding on N-terminus of the receptor and the intracellular loops and C-terminus interact with signaling proteins, such as G-proteins. The extracellular loops also contain several sites for post-translational modification and are involved in ligand binding. The third intracellular loop is the largest and contains phosphorylation sites for signaling regulation. As the name suggests, GPCRs are coupled to G-proteins that are heterotrimeric in nature.Heterotrimeric G-proteins consist of three subunits: alpha, beta, and gamma.[8] Upon the binding of a ligand to the extracellular domain of the GPCR, a conformational change is induced in the receptor that allows it to interact with the alpha-subunit of the G-protein. Following this interaction, the G-alpha subunit exchanges GDP for GTP, becomes active, and dissociates from the beta and gamma subunits. The free alpha subunit is then able to activate downstream signaling pathways (detail more in interactions and pathway).
ADRB-1 is activated by the catecholamines adrenaline and noradrenaline. Once these ligands bind, the ADRB-1 receptor activates several different signaling pathways and interactions. Some of the most well-known pathways are:
Adenylyl cyclase: When a ligand binds to the ADRB-1 receptor, the alpha-subunit of the heterotrimeric G-protein gets activated, which in turn, activates the enzymeadenylyl cyclase.Adenylyl cyclase then catalyzes the conversion ofATP tocyclic AMP (cAMP), which activates downstream effectors such asProtein Kinase A (PKA).
cAMP activation of PKA: cAMP generated by adenylyl cyclase activates PKA, which then phosphorylates numerous downstream targets such as ion channels, other enzymes, andtranscription factors .
Beta-arrestins: Activation of the ADRB-1 receptor can lead to the recruitment ofBeta-arrestins, which are used to activate signaling pathways independent of G-proteins. An example of an independent pathway is the MAPK (mitogen-activated protein kinase) pathways.
Calcium signaling: ADRB-1 signaling also activates theGq/11 family of G proteins, which is a subfamily of heterotrimeric G proteins that activatesphospholipase C (PLC). PLC cleavesphosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengersinositol 1,4,5-triphosphate (IP3) anddiacylglycerol (DAG). IP3 binds to IP3 receptors on the endoplasmic reticulum, which then leads to the release of calcium ions (Ca2+) into the cytoplasm, resulting in the activation of downstream signaling pathways.[9]
Other pathways that the ADRB-1 receptor plays an important role in:
Regulation of peripheral clock and central circadian clock synchronization: Thesuprachiasmatic nucleus (SCN) receives light information from the eyes and synchronizes the peripheral clocks to the central circadian clock through the release of different neuropeptides and hormones.[13] ADRB-1 receptors can play a role in modulating the release of neuropeptides likevasoactive intestinal peptide (VIP) andarginine vasopressin (AVP) from the SCN, which can then synchronize peripheral clocks.
Regulation of glucose metabolism: The regulation of glucose metabolism is known to be linked with ADRB-1 receptor signaling.[14] The signal transduction pathway that is activated through the ADRB-1 receptor can regulate the expression ofclock genes andglucose transporters. The disregulation of ADRB-1 receptor signaling has been implicated in metabolic disorders such as diabetes and obesity.
ADRB-1 receptor and rhythmic control of immunity: Circadian oscillations in catecholamine signals influence various cellular targets which express adrenergic receptors, including immune cells.[13] The adrenergic system regulates a range of physiological functions which are carried out throughcatecholamine production. Humans are found to have low circulating catecholamine levels during the night and high levels during the day, while rodents exhibit the opposite pattern. Studies demonstrating the patterns ofnorepinephrine levels indicate that there is no circadian rhythmicity. Circulating rhythms in epinephrine, however, appear to be circadian and are regulated by theHPA axis:
Cyclic variation in HPA signals are likely important in driving diurnal oscillations in adrenaline.
The most well-characterized means through which adrenergic signals exert circadian control over immunity is by cell-trafficking regulation. Variation in the number of white blood cells seemed to be linked to adrenergic function.
Cardiac rhythm and cardiac failure: The β-AR signaling pathway serves as a primary component of the interface between thesympathetic nervous system and thecardiovascular system.[15] The β-AR pathway dysregulation has been implicated in the pathogenesis of heart failure. It has been found that certain changes to β-AR signaling result in reduced levels of β1-AR, by up to 50%, while levels of β2-AR remain constant. Other intracellular changes include a significant, sharp increase of GαI levels, and increased βARK1 activity. These changes suggest sharp decreases in β-AR signaling, likely due to sustained, elevated levels of catecholamines.
Gs exerts its effects via two pathways. Firstly, it directly opensL-type calcium channels (LTCC) in the plasma membrane. Secondly, it rendersadenylate cyclase activated, resulting in an increase ofcAMP, activatingprotein kinase A (PKA) which in turn phosphorylates several targets, such asphospholamban, LTCC,Troponin I (TnI), andpotassium channels. The phosphorylation of phospholamban deactivates its own function which normally inhibitsSERCA on thesarcoplasmic reticulum (SR) in cardiac myocytes. Due to this, more calcium enters the SR and is therefore available for the next contraction. LTCC phosphorylation increases its open probability and therefore allows more calcium to enter the myocyte upon cell depolarisation. Both of these mechanisms increase the available calcium for contraction and therefore increaseinotropy. Conversely, TnI phosphorylation results in its facilitated dissociation of calcium fromtroponin C (TnC) which speeds the muscle relaxation (positivelusitropy). Potassium channel phosphorylation increases its open probability which results in shorterrefractory period (because the cell repolarises faster), also increasinglusitropy. Furthermore, in nodal cells such as in the SA node, cAMP directly binds to and opens theHCN channels, increasing their open probability, which increaseschronotropy.[6]
Amissense variant in the ADRB-1 coding sequence was initially identified as causingfamilial natural short sleep[16] in one affected family. However, subsequentbiobank research showed that other carriers of this mutation or of different high-impact mutations in the same gene did not exhibit any change in sleep duration, indicating that the cause of the short sleeper phenotype in this family had a different basis.[17]
One of thesingle nucleotide polymorphisms (SNPs) in ADRB-1 is the change from acytosine to aguanine, resulting in a protein switch fromarginine (389R) toglycine (389G) at the 389 codon position.Arginine at codon 389 is highly preserved across species and this mutation happens in the G-protein binding domain of ADRB-1, one of the key functions of ADRB-1 protein, so it is likely to lead to functional differences. In fact, this SNP causes dampened efficiency and affinity in agonist-promoted receptor binding.[18]
Another common SNP occurs at codon position 49, with a change of serine (49S) toglycine (49G) in the N-terminus sequence of ADRB-1. The 49S variant is shown to be more resistant to agonist-promoted down regulation and short intervals of agonist exposure. The receptor of the 49G variant is always expressed, which results in high coupling activity withadenylyl cyclase and increased sensitivity to agonists.[18]
Both of these SNPs have relatively high frequencies among populations and are thought to affect cardiac functions. Individuals who are homozygous for the 389R allele are more likely to have higher blood pressure and heart rates than others who have either one or two copies of the 389G allele. Additionally, patients with heart diseases that have a substitution ofglycine forserine at codon 49 (49S > G) show improved cardiac functions and decreased mortality rate.[19] The cardiovascular responses induced by this polymorphism in the healthy population are also examined. Healthy individuals with aglycine at codon 49 show better cardiovascular functions at rest and response to maximum heart rate during exercise, evident for thecardioprotection related to this polymorphism.[19]
Because ADRB-1 plays such a critical role in maintaining blood pressure homeostasis and cardiac output, many medications treat these conditions by either potentiating or inhibiting the functions of the ADRB-1.Dobutamine is one of the adrenergic drugs and agonists that selectively bind to ADRB-1 and is often used in treatments ofcardiogenic shock andheart failure.[20] It is also important to note the use of illicit drug for ADRB-1 sincecocaine,beta-blocking agents, or other sympathetic stimulators may cause a medical emergency.
ADRB-1 agonists mimic or initiate a physiological response when bound to a receptor.Isoprenaline has higher affinity for β1 thanadrenaline, which, in turn, binds with higher affinity thannoradrenaline at physiologic concentrations. As ADRB-1 increases cardiac output, selective agonists clinically function as potential treatments for heart failure.Selective agonists to the beta-1 receptor are:
Denopamine is used in the treatment of angina and has potential uses to treat congestive heart failure and pulmonary oedema.
Xamoterol[12] (cardiac stimulant) acts as a partial agonist that improves heart function in studies with cardiac failure. Xamoterol plays a role in modulating the sympathetic nervous system, but does not have any agonistic action on beta-2 adrenergic receptors.
Isoproterenol is a nonselective agonist that potentiates the effects of agents like adrenaline and norepinephrine to increase heart contractility.
ADRB-1 antagonists are a class of drugs also referred to asBeta Blockersβ1-selective antagonists are used to manage abnormal heart rhythms and block the action of substances like adrenaline on neurons, allowing blood to flow more easily which lowers blood pressure and cardiac output. They may also shrink vascular tumors. Some examples of Beta-Blockers include:
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Overview of all the structural information available in thePDB forUniProt:P08588 (Beta-1 adrenergic receptor) at thePDBe-KB.
