Beta-1 adrenergic receptor

Protein coding gene in the species Homo sapiens

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 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:

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 Gq/11 family of G proteins, which is a subfamily of heterotrimeric G proteins that activates phospholipase C (PLC). PLC cleaves phosphatidylinositol 4,5 bisphosphate (PIP2) into the second messengers inositol 1,4,5 triphosphate (IP3) and 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.

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. 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. 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. 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. 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.