Adrenergic Receptors

Adrenergic receptors (also known as adrenoceptors, ARs) are membrane-bound proteins that mediate the peripheral and central actions of norepinephrine and epinephrine. ARs belong to the guanine nucleotide-binding G protein–coupled receptor (GPCR).
By virtue of their location, either presynaptically or postsynaptically on neurons or effector organs such as the heart, vasculature, and adipose tissue. This class of receptors mediates a wide range of important homeostatic responses.
Adrenergic receptors were originally divided into two major groups: α- and β-adrenoceptors (ARs).

  • α-ARs demonstrate weak responses to the synthetic agonist isoproterenol but are very responsive to epinephrine and norepinephrine.
  • β-ARs respond potently to (agonist) isoproterenol and are less sensitive to epinephrine and norepinephrine; (antagonist) propranolol.
During more recent years, both new pharmacological tools and the cloning of genes have revealed nine different AR subtypes:
  • three α1-ARs (α1A, α1B, and α1D),
  • three α2-ARs (α2A/D, α2B, and α2c), and
  • three β-ARs (β1, β2, and β3).1 Encyclopedia of Endocrine Diseases

β-Adrenoceptors are the best characterized and predominant adrenoceptors in the lung, with both β1 and β2 receptors being widely distributed. β2-Adrenoceptors are an important therapeutic target and their polymorphisms may influence the response to β2 agonist treatment. Their numbers and functions are regulated by β-agonist stimulation and by drugs, such as corticosteroids, and cytokines.
α-Adrenoceptors are found on vascular smooth muscle, presynaptic nerve endings, airways, and submucus glands, and they may help to condition inspired air.
There is evidence for D1 dopamine expression on alveolar cells, where they help to clear lung edema, and for D2 receptors on sensory nerves in the lung, where they may modulate neurogenic inflammation and reflex-mediated symptoms. 2 Encyclopedia of Respiratory Medicine

Adrenergic Signaling

Adrenergic receptors are membrane receptors that activate heterotrimeric G proteins following the binding of a ligand. GPCRs consist of one extracellular N-terminal domain, seven membrane-spanning domains, three intra- and three extracellular loops, and one intracellular C-terminal tail (Fig. 1).
These heptahelical trans-membrane sensors account for approximately 4% of the total protein-coding genome and are considered the most important drug targets in medicine and physiology. G proteins typically stimulate (via Gs protein) or inhibit (via Gi protein) the enzyme adenylyl-cyclase or activate (via Gq protein) phospholipase C (PLC).
GPCR signaling is terminated by phosphorylation of the intracellular domains of the receptor by the family of G protein–coupled receptor kinases (GRKs). GRK-mediated phosphorylation increases the affinity of GPCRs for the arrestin class of proteins, which uncouples the phosphorylated receptor from G protein and successively targets the receptor for internalization. Downregulation of GPCRs reduces the functional activity of classical signaling paradigms up to 80% (Fig. 1).

Figure 1. G protein–coupled receptor (GPCR) activation and regulation.
  • (A) Binding of a GPCR ligand to the extracellular side of the receptor enables the exchange of GDP to GTP by the α subunit of the G protein.
  • (B) The GTP-bound α subunit then acts on a second messenger-releasing enzyme such as adenylate cyclase (ACA) (Gαs) or phospholipase C (PLC) (Gαq), leading to their activation.
  • (C) Second-messenger molecules such as cAMP and inositol-1,4,5-triphosphate (InsP3) are direct products of enzymatic conversion of ATP and phosphatidylinositol-4,5-bisphosphate (PIP2) respectively, whereas cytosolic Ca2+ is released upon activation of reticular calcium channels.
  • (D) Second-messenger molecules can trigger cascade reactions that will lead to a downstream biological event (frequently gene expression regulation).
  • (E) GPCR responsive elements such as protein kinases (PKs) or G protein–coupled receptor kinases (GRKs) phosphorylate the intracellular side of the receptor and decouple the G protein by steric exclusion.
  • (F) β-Arrestins can recognize the phosphorylated GPCR and trigger the internalization process.
  • (G) Modifications on the β-arrestin molecule such as dephosphorylation or ubiquitination define the fate of the internalized molecule either to recycling or degradation, respectively.
Adapted from Martins SA, Trabuco JR, Monteiro GA, Chu V, Conde JP, Prazeres DM. Towards the miniaturization of GPCR-based live-cell screening assays. Trends Biotechnol 2012;30(11):566–74. (10.1016/j.tibtech.2012.07.004).
Phenylephrine is a selective pharmacological agonist of αAR while isoproterenol is considered a nonselective agonist for βAR.

  • The subfamily of α1AR (Gq coupled receptors) consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-AR.
  • The α2AR subfamily (coupled to Gi) comprises three subtypes: α2A-, α2B-, and α2C-AR.
  • Some species other than humans express a fourth α2D-AR as well.
In the βAR family there are three receptor subtypes:
  • β1AR is found at its highest levels in the heart,
  • β2AR is distributed extensively throughout the body,
  • β3AR is mainly expressed in the white and brown adipose tissue.
All three βARs couple primarily to Gαs and subsequent cAMP-related pathways, although under certain conditions can also couple to Gαi. β2AR and β3AR signaling can also occur via G protein independent mechanisms. In particular, cardiac β3AR causes negative inotropic effects mainly mediated by activation of nitric oxide (NO) synthase, serving thereby as a brake in sympathetic overstimulation. These paradigms of signaling can be observed in the same cell type based on the functional state of the cell. Henceforth, the response to GPCR stimulus can be modified by various conditions, including chronic stimulation, acidosis, cell hypoxia, and aging. 3 Endocrinology of the Heart in Health and Disease

References:

  1. Linda F. Hayward, Eileen M. Hasser, Encyclopedia of Endocrine Diseases, 2004
  2. A.E. Tattersfield, Encyclopedia of Respiratory Medicine, 2006
  3. M. Ciccarelli, ... G. Santulli, Endocrinology of the Heart in Health and Disease, 2017
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