ADRENERGIC RECEPTORS: LOCATION, FUNCTIONS AND CLASSIFICATION - BIOLOGY - 2025

The adrenergic receptors are protein molecules located on the cell membranes upon which the catecholamines adrenalin (A) and noradrenaline (NA) exert their effects. Its name derives from the name of the first of these substances, adrenaline.

Adrenaline is in turn the name by which a substance that facilitates organic responses related to fight or flight reactions has been known since the 19th century, and which was discovered to be elaborated and secreted by cells in the marrow of small glands located in the upper pole of each kidney.

Signaling pathways of adrenergic receptors (Source: Sven Jähnichen. Partially translated by Mikael Häggström / CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/) via Wikimedia Commons)

Due to their anatomical relationships with the kidney, these glands were called "adrenal", to indicate their position in the upper part of the kidneys, or also adrenals, to indicate their closeness or contiguous relationship with these organs.

Although the etymology of the Greek “epi” (above) and “nephros” (kidney) did not have much influence on the naming of the glands, it did have an impact on the naming of the mentioned substances that are also known as epinephrine and norepinephrine.

It was, however, the Latin words that prevailed as roots to establish the nomenclature of all the factors associated with these two substances, and that is why we speak of adrenergic or noradrenergic cells, fibers, systems or receptors, and not epinephrinergic or norepinephrinegic.

Adrenergic receptors belong to the class of heterotrimeric G protein-coupled metabotropic receptors. They are long integral proteins that extend from the outside of the cell and have 7 α-helix segments that successively cross the thickness of the membrane, form loops outside and inside the membrane and end at a cytoplasmic end.

Location of adrenergic receptors

Adrenergic receptors are located in the central nervous system and in many of the visceral components of the body.

In the central nervous system

In the central nervous system (CNS), they are located in the postsynaptic membranes of synapses formed by axon endings that originate in adrenergic or noradrenergic cell nuclei of the brain stem.

With the exception of β3 receptors, all the types of adrenergic receptors described to date have been identified in the central nervous system, especially in the terminal areas of noradrenergic projections originating in the cerulean locus, including the optic thalamus, the hypothalamus, the limbic system. and the cerebral cortex.

In viscera

Regarding the visceral adrenergic receptors, they are of various types and are located for the most part in the membranes of the visceral effector cells on which the postganglionic axons of the sympathetic division of the autonomic nervous system terminate, releasing mainly norepinephrine.

Components of the cardiovascular system are included here, such as the cells of the excitation-conduction system of the heart and the atrial and ventricular working myocardium, as well as the arteriolar smooth muscle of vessels in the skin and mucosa, abdominal region, skeletal muscle, circulation. coronary artery, veins, erectile tissue of sexual organs and brain.

Gastrointestinal tract

The gastrointestinal tract has adrenergic receptors in its longitudinal and circular muscles responsible for peristaltic movements, and also at the level of the sphincters.

They are expressed by liver cells and the α and β cells of the islets of Langerhans of the pancreas, the latter associated with the production and release of glucagon and insulin, respectively.

Genito-urinary system

Regarding the genito-urinary system, its presence is detected in the juxtaglomerular cells and in the tubular cells of the kidney, in the detrusor muscle and in the trigone of the bladder (internal sphincter), in the seminal vesicles, the prostate, the duct deferent and uterus.

They are also present in other structures such as the pupil dilator muscle, the tracheo-bronchial smooth muscles, the piloerector muscles of the skin, the salivary glands of mucous secretion such as the submaxillary, the pineal gland and the adipose tissue.

Some of these receptors are also located on visceral cells in areas far from sympathetic endings and that are therefore not stimulated by norepinephrine, the main substance released by these endings, but by adrenaline, the main substance released by the adrenal medulla and it acts as a hormone.

Features

Adrenergic receptors mediate the effects that the sympathetic nervous system unleashes on the different visceral effector components on which it acts by modifying their level of activity.

These effects are as varied as their distribution in the visceral component is varied and the different types and subtypes of receptors present in each tissue of the body are varied.

The functions are associated with the responses triggered in the effectors by the activation of adrenergic receptors when these bind to their ligands (adrenaline or noradrenaline).

These responses include the contraction or relaxation of smooth muscle (depending on the visceral sector considered), the secretion or inhibition of substance secretion, and some metabolic actions such as lipolysis or glycogenolysis.

Classification of adrenergic receptors

Pharmacological criteria have been used to make their identification and classification. One of them consists in determining the relative effectiveness of equimolar doses of substances that reproduce (sympathomimetic) the effects of the activation of the different types of receptors, while the other uses sympatholytic substances to block these effects.

With these procedures, along with others such as the determination of their molecular structures and the cloning of their genes, it has been possible to determine the existence of two large categories of adrenergic receptors:

- alpha (α) and

- beta (β) receptors.

Of the former, two subtypes have been identified: α1 and α2, and of the latter subtypes β1, β2 and β3.

Both norepinephrine and epinephrine have the same intensity of effects on α1 and β3 receptors. Norepinephrine has stronger effects on β1 receptors than epinephrine; while adrenaline is more potent than norepinephrine on α2 and β2.

- Alpha adrenergic receptors

Α1 receptors

These receptors are found in the smooth muscle of most vascular beds, in the sphincters of the gastrointestinal tract and in the internal sphincter of the bladder, in the pupil dilator muscle, in the piloerector muscle, in the seminal vesicles, the prostate, the vas deferens, the submaxillary salivary gland and the renal tubules.

The activation of all these effectors depends on the level of cytosolic calcium (Ca2 +), which in turn depends on its release from its storage site in the sarcoplasmic reticulum; release that occurs when calcium channels are opened activated by a molecule called inositol triphosphate or IP3.

The α1 receptors are coupled to a G protein called Gq, with three subunits: αq, β, and γ.

When the receptor is activated by its ligand, the protein is dissociated into a βγ and an αq component, which activates the phospholipase enzyme. It produces diacylglycerol from membrane inositol diphosphate (PIP2). Diacylglycerol activates protein kinase C and IP3, which favors the release of calcium into the cytoplasm.

Α2 receptors

Their presence has been described in the longitudinal and circular musculature of the gastrointestinal tract, where they act by inhibiting its motility. They are also localized in pancreatic β cells where they inhibit insulin secretion.

They are also expressed as autoreceptors at the level of the presynaptic membrane of the sympathetic noradrenergic varicosities, where they are activated by released norepinephrine and act as a negative feedback mechanism, inhibiting the subsequent secretion of the neurotransmitter.

The α2 receptors work coupled to a Gi protein, so called because its alpha subunit (αi), when separated from the βγ complex, produces an inhibition of adenyl cyclase and reduces intracellular cAMP levels, thereby reducing the activity of protein kinase A (PKA). Hence the inhibitory effect of these receptors.

- Beta adrenergic receptors

Β1 receptors

They are located at the level of the pacemaker cells of the sinoatrial node, as well as in the cardiac excitation conduction system and in the contractile myocardium, in whose locations they promote increases in frequency (chronotropism +) and conduction velocity (dromotropism +), the force of contraction (inotropism +) and the relaxation rate (lusotropism +) of the heart.

They have also been described in the musculature of the gastrointestinal tract (which they inhibit) and in the cells of the juxtaglomerular apparatus of the kidney (where they promote renin secretion).

All beta-like receptors (β1, β2, and β3) are Gs protein coupled. The subscript "s" refers to the stimulatory activity of the enzyme adenyl cyclase, which is triggered when the receptor interacts with its ligand, releasing the αs subunit.

The cAMP activates PKA and this is responsible for phosphorylating proteins such as channels, pumps or enzymes that mediate responses to receptors.

Β2 receptors

They have been revealed at the level of the smooth muscle located in the arterioles of skeletal muscle, in the detrusor muscle of the bladder, in the uterus and in the tracheobronchial muscles, inducing relaxation in all of them.

Diagram of the crystal structure of a beta 2-type adrenergic receptor (Source: S. Jähnichen / Public domain via Wikimedia Commons)

They are also expressed in the pineal gland (where they promote melatonin synthesis), in the liver (where they promote glycolysis and gluconeogenesis), and in adipose tissue cells (where they promote lipolysis and the release of fatty acids into the blood) free).

Β3 receptors

These are the last to have been identified. As already mentioned above, their presence does not occur in the central nervous system, but is restricted to the periphery of the body, where they are located exclusively at the level of brown adipose tissue cells and are directly involved in the production of heat. through lipid catabolism in this tissue.

References

1. Ganong WF: Neurotransmitters and Neuromodulators, in: Review of Medical Physiology, 25th ed. New York, McGraw-Hill Education, 2016.
2. Guyton AC, Hall JE: The Autonomic Nervous System and the Adrenal Medulla, in: Textbook of Medical Physiology, 13th ed; AC Guyton, JE Hall (eds). Philadelphia, Elsevier Inc., 2016.
3. Jänig W: Vegetatives Nervensystem, in: Physiologie des Menschen mit Pathophysiologie, 31 th ed; RF Schmidt et al (eds). Heidelberg, Springer Medizin Verlag, 2010.
4. Seller H: Neurovegetative Regulationen, in: Physiologie, 6th ed; R Klinke et al (eds). Stuttgart, Georg Thieme Verlag, 2010.
5. Siegelbaum SA, Clapham DE, Schwartz JH: Modulation of Synaptic Transmission: Second Messengers, In: Principles of Neural Science, 5th ed; E Kandel et al (eds). New York, McGraw-Hill, 2013.