Beta-1 adrenergic receptor
The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, can refer to either the protein-encoding gene (gene ADRB1) or one of the four
Historical Context
General Information
Structure
ADRB-1 is a
Function
Pathways
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 enzyme adenylyl cyclase. Adenylyl cyclase then catalyzes the conversion of ATP to cyclic AMP (cAMP), which activates downstream effectors such as Protein 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, and transcription factors .
- Beta-arrestins: Activation of the ADRB-1 receptor can lead to the recruitment of Beta-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 the diacylglycerol(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.
Summary of Interactions
Actions of the β1 receptor include:
System | Effect | Tissue |
---|---|---|
Muscular | Increases cardiac output | Cardiac muscle |
Increases heart rate (chronotropic effect) | Sinoatrial node (SA node) [9] | |
Increases inotropic effect)
|
Cardiac muscle | |
Increases contractility and automaticity
|
Ventricular cardiac muscle [9]
| |
Increases conduction and automaticity
|
Atrioventricular node (AV node)[9] | |
Relaxation | Urinary bladder wall[10] | |
Exocrine | Releases renin | Juxtaglomerular cells.[9]
|
Stimulates viscous, amylase-filled secretions | ||
Other | Lipolysis | Adipose tissue[9] |
The receptor is also present in the cerebral cortex.
Other pathways that play ADRB-1 receptor plays an important role in:
- Regulation of peripheral clock and central circadian clock synchronization: The arginine 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.[13] The signal transduction pathway that is activated through the ADRB-1 receptor can regulate the expression of clock genes and glucose 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.[12] The adrenergic system regulates a range of physiological functions which are carried out through catecholamine 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 of norepinephrine levels indicate that there is no circadian rhythmicity. Circulating rhythms in epinephrine, however, appear to be circadian and are regulated by the HPA 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 the cardiovascular system.[14]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.
Mechanism in cardiac myocytes
Clinical Significance
Familial Natural Short Sleep (FNSS)
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.[15] 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.[15]
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.[16] 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.[15] 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.
Polymorphisms in ADRB-1
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.[17]
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.[17]
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.[18] 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.[18]
Pharmaceutical Interventions
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.[19] 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.
Agonists
ADRB-1 agonists mimic or initiate a physiological response when bound to a receptor.
- Denopamine is used in the treatment of angina and has potential uses to treat congestive heart failure and pulmonary oedema.
- Dobutamine[11] (in cardiogenic shock) is a beta-1 agonist that treats cardiac decompensation.
- Xamoterol[11] (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.
Antagonists
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:
- arrhythmias)
- arrhythmias and myocardial infarction)
- Betaxolol (in hypertension and glaucoma)
- ischemic heart diseases)
- arrhythmias)
- coronary heart disease, myocardial infarction and heart failure)
- Nebivolol (in hypertension)
- Vortioxetine (antidepressant)
See also
- Other adrenergic receptors
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000043591 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035283 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: ADRB1 adrenergic, beta-1-, receptor".
- ^ )
- PMID 19458711.
- ^ Nestler EJ, Duman RS (1999). "Heterotrimeric G Proteins". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Edition.
- ^ ISBN 978-0-87893-725-7.
- PMID 23200975.
- ^ ISBN 978-0-443-07145-4. Page 163
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- ^ PMID 16120061.
- ^ PMID 30627284.
- PMID 30480963, retrieved 2023-04-26
- ^ American Society of Health-System Pharmacists, Inc. (2005-01-01). "Bisoprolol". MedlinePlus Drug Information. U.S. National Library of Medicine, National Institutes of Health. Archived from the original on 2008-05-20. Retrieved 2008-06-06.
Further reading
- Frielle T, Kobilka B, Lefkowitz RJ, Caron MG (July 1988). "Human beta 1- and beta 2-adrenergic receptors: structurally and functionally related receptors derived from distinct genes". Trends in Neurosciences. 11 (7): 321–324. S2CID 140209236.
- Muszkat M (August 2007). "Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9". Clinical Pharmacology and Therapeutics. 82 (2): 215–218. S2CID 10381767.
- Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, et al. (February 1990). "Chromosomal organization of adrenergic receptor genes". Proceedings of the National Academy of Sciences of the United States of America. 87 (4): 1516–1520. PMID 2154750.
- Forse RA, Leibel R, Gagner M (January 1989). "The effect of Escherichia coli endotoxin on the adrenergic control of lipolysis in the human adipocyte". The Journal of Surgical Research. 46 (1): 41–48. PMID 2536864.
- Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK (November 1987). "Cloning of the cDNA for the human beta 1-adrenergic receptor". Proceedings of the National Academy of Sciences of the United States of America. 84 (22): 7920–7924. PMID 2825170.
- Stiles GL, Strasser RH, Lavin TN, Jones LR, Caron MG, Lefkowitz RJ (July 1983). "The cardiac beta-adrenergic receptor. Structural similarities of beta 1 and beta 2 receptor subtypes demonstrated by photoaffinity labeling". The Journal of Biological Chemistry. 258 (13): 8443–8449. PMID 6305985.
- Hoehe MR, Otterud B, Hsieh WT, Martinez MM, Stauffer D, Holik J, et al. (June 1995). "Genetic mapping of adrenergic receptor genes in humans". Journal of Molecular Medicine. 73 (6): 299–306. S2CID 27308274.
- Elies R, Ferrari I, Wallukat G, Lebesgue D, Chiale P, Elizari M, et al. (November 1996). "Structural and functional analysis of the B cell epitopes recognized by anti-receptor autoantibodies in patients with Chagas' disease". Journal of Immunology. 157 (9): 4203–4211. S2CID 44386743.
- Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, et al. (November 1998). "SH3 binding domains in the dopamine D4 receptor" (PDF). Biochemistry. 37 (45): 15726–15736. PMID 9843378.
- Mason DA, Moore JD, Green SA, Liggett SB (April 1999). "A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor". The Journal of Biological Chemistry. 274 (18): 12670–12674. PMID 10212248.
- Moore JD, Mason DA, Green SA, Hsu J, Liggett SB (September 1999). "Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C". Human Mutation. 14 (3): 271. S2CID 8860722.
- Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, et al. (October 1999). "Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12559–12564. PMID 10535961.
- Podlowski S, Wenzel K, Luther HP, Müller J, Bramlage P, Baumann G, et al. (2000). "Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy?". Journal of Molecular Medicine. 78 (2): 87–93. S2CID 1072602.
- Shiina T, Kawasaki A, Nagao T, Kurose H (September 2000). "Interaction with beta-arrestin determines the difference in internalization behavor between beta1- and beta2-adrenergic receptors". The Journal of Biological Chemistry. 275 (37): 29082–29090. PMID 10862778.
- Hu LA, Tang Y, Miller WE, Cong M, Lau AG, Lefkowitz RJ, et al. (December 2000). "beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors". The Journal of Biological Chemistry. 275 (49): 38659–38666. PMID 10995758.
- Börjesson M, Magnusson Y, Hjalmarson A, Andersson B (November 2000). "A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure". European Heart Journal. 21 (22): 1853–1858. PMID 11052857.
- Xu J, Paquet M, Lau AG, Wood JD, Ross CA, Hall RA (November 2001). "beta 1-adrenergic receptor association with the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 (MAGI-2). Differential regulation of receptor internalization by MAGI-2 and PSD-95". The Journal of Biological Chemistry. 276 (44): 41310–41317. PMID 11526121.
- Hu LA, Chen W, Premont RT, Cong M, Lefkowitz RJ (January 2002). "G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95". The Journal of Biological Chemistry. 277 (2): 1607–1613. PMID 11700307.
- Ranade K, Jorgenson E, Sheu WH, Pei D, Hsiung CA, Chiang FT, et al. (April 2002). "A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate". American Journal of Human Genetics. 70 (4): 935–942. PMID 11854867.
Further reading
- Alhayek S, Preuss CV (August 2022). "Beta 1 Receptors.". StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. PMID 30422499.
External links
- Human ADRB1 genome location and ADRB1 gene details page in the UCSC Genome Browser.
- "β1-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-06-06. Retrieved 2008-11-25.
- Overview of all the structural information available in the PDB for UniProt: P08588 (Beta-1 adrenergic receptor) at the PDBe-KB.