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

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

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).

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 Gα_s and subsequent cAMP-related pathways, although under certain conditions can also couple to Gα_i. 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

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