|, ADRB1R, B1AR, BETA1AR, RHR, adrenoceptor beta 1, FNSS2|
The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, can either refer to the protein-encoding gene (gene ADRB1) or one of the four adrenergic receptors. It is a G-protein coupled receptor associated with the Gs heterotrimeric 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 or sympathins while studying the sympathetic nervous system in 1933. These E and I sympathins were involved with excitatory and inhibitory responses. In 1948, Raymond Ahlquist published a manuscript in the American 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 a transmembrane protein that belongs to the G-Protein-Coupled Receptor (GPCR) family. GPCRs play a key role in cell signaling pathways and are primarily known for their seven 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. 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:
Actions of the β1 receptor include:
|Muscular||Increases cardiac output||Cardiac muscle|
|Increases heart rate (chronotropic effect)||Sinoatrial node (SA node) |
|Increases atrial contractility (inotropic effect)||Cardiac muscle|
|Increases contractility and automaticity||Ventricular cardiac muscle |
|Increases conduction and automaticity||Atrioventricular node (AV node)|
|Relaxation||Urinary bladder wall|
|Exocrine||Releases renin||Juxtaglomerular cells.|
|Stimulates viscous, amylase-filled secretions|
The receptor is also present in the cerebral cortex.
Other pathways that play ADRB-1 receptor plays an important role in:
Gs exerts its effects via two pathways. Firstly, it directly opens L-type calcium channels (LTCC) in the plasma membrane. Secondly, it renders adenylate cyclase activated, resulting in an increase of cAMP, activating protein kinase A (PKA) which in turn phosphorylates several targets, such as phospholamban, LTCC, Troponin I (TnI), and potassium channels. The phosphorylation of phospholamban deactivates its own function which normally inhibits SERCA on the sarcoplasmic 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 increase inotropy. Conversely, TnI phosphorylation results in its facilitated dissociation of calcium from troponin C (TnC) which speeds the muscle relaxation (positive lusitropy). Potassium channel phosphorylation increases its open probability which results in shorter refractory period (because the cell repolarises faster), also increasing lusitropy. Furthermore, in nodal cells such as in the SA node, cAMP directly binds to and opens the HCN channels, increasing their open probability, which increases chronotropy.
A rare mutation that changes a cytosine to a thymine in the ADRB-1 coding sequence results in a protein switch to valine from alanine at amino acid position 187 (A187) and leads to the FNSS behavior trait, where mutation carriers naturally wake up after only 4 to 6.5 hours of sleep. The ADRB-1 protein is involved in a cyclic adenosine monophosphate (cAMP)-mediated signaling pathway, and the ADRB1-A187V mutated protein leads to a lower cAMP production than the wild-type protein, given the same isoproterenol treatment, a nonselective agonist of ADRB-1. It was also discovered that the mutated protein is less stable most likely due to post-translational modifications, as shown in an ADRB1 knockin experiment where a mutated ADRB-1 gene replaces the wild-type with CRISPR technology and the protein level displays a decrease while the mRNA level remains high.
Mice with a heterozygous ADRB1-A187V mutation show increased activity time and shorter intervals of rapid eye movement (REM) sleep and non-REM sleep, suggesting that the mutation causes short sleep. In another experiment, the ADRB1-A187V mutation restored REM sleep in tau mice (PS19) and reduced tau accumulation, which can promote brain cell damage and death, in the locus coeruleus (LC) of PS19 mice. Furthermore, a high expression level of ADRB-1 protein is observed in the dorsal pons (DP), referred to as ADRB1+ neurons. The activity of these ADRB1+ neurons in DP is shown to be closely linked with the sleep-wake behavior and altered by the ADRB1-A187V mutation. The ADRB1+ neurons can be either inhibitory or excitatory. In the brains of mutant mice, the percentage of ADRB1+ neurons that may be inhibited by agonists reduces significantly while the percentage of neurons that may be excited by agonists remains relatively unchanged. It is thus speculated that the ADRB-1 protein has an inhibitory and an excitatory function, with the inhibitory function being more sensitive to its decreased protein levels and the excitatory function being less sensitive. Although the ADRB1-A187V mutation leads to lower protein levels, as discussed above, overall there are fewer ADRB1+ neurons inhibited, corresponding to the higher total activity of DP ADRB1+ neurons observed in mutant mice. These results collectively indicate that high activity levels in ADRB1+ neurons leads to shorter sleep or FNSS.
One of the single nucleotide polymorphisms (SNPs) in ADRB-1 is the change from a cytosine to a guanine, resulting in a protein switch from arginine (389R) to glycine (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.
Another common SNP occurs at codon position 49, with a change of serine (49S) to glycine (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 with adenylyl cyclase and increased sensitivity to agonists.
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 of glycine for serine at codon 49 (49S > G) show improved cardiac functions and decreased mortality rate. The cardiovascular responses induced by this polymorphism in the healthy population are also examined. Healthy individuals with a glycine at codon 49 show better cardiovascular functions at rest and response to maximum heart rate during exercise, evident for the cardioprotection related to this polymorphism.
Because ADRB-1 play 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 of cardiogenic shock and heart failure. It is also important to note the use of illicit drug for ADRB-1 since cocaine, 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 than adrenaline, which, in turn, binds with higher affinity than noradrenaline 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:
ADRB-1 antagonists are a class of drugs also referred to as Beta Blockers β1-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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