Adrenergic receptor

Adrenaline

Noradrenaline

The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline (norepinephrine) and adrenaline (epinephrine). Although dopamine is a catecholamine, its receptors are in a different category. Dopamine has been used as a neurotransmitter since the beginning of nerve system evolution. Probably to fine tune the dopamine system the adrenergic receptors were developed to sense the metabolites of dopamine - noradrenaline in early vertebrates, and octopamine in arthropods. Further development of vertebrate adrenergic receptors made some of them more sensitive to noradrenaline´s degradation product adrenaline. But still they have some sensitivity to dopamine - a fact that is sometimes used in medicine.

Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (i.e. the fight-or-flight response). For instance, the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow diverted from other non-essential organs to skeletal muscle.

Subtypes

There are two main groups of adrenergic receptors, α and β, with several subtypes.

• α receptors have the subtypes α₁ (a G_q coupled receptor) and α₂ (a G_i coupled receptor). Phenylephrine is a selective agonist of the α receptor.
• β receptors have the subtypes β₁, β₂ and β₃. All three are linked to G_s proteins, which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a selective agonist.

Epinephrine binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal (more details...)

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α₁, α₂ or β-adrenergic receptors. α₁ couples to G_q, which results in increased intracellular Ca²⁺ which results in smooth muscle contraction. α₂, on the other hand, couples to G_i, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle relaxation. β receptors couple to G_s, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

Roles in circulation

Adrenaline reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, producing an overall vasodilation.

Comparison

^†There is no α_1C receptor. At one time, there was a subtype known as C, but was found to be identical to one of the previously discovered subtypes. To avoid confusion, naming was continued with the letter D.

α receptors

α receptors have several functions in common, but also individual effects. Common (or still unspecified) effects include:

• Vasoconstriction of arteries to heart (coronary artery).^[2]
• Vasoconstriction of veins^[3]
• Decrease motility of smooth muscle in gastrointestinal tract^[4]

α₁ receptor

Alpha1-adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5-biphosphate (PIP2) which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic retuculum thus changing the calcium content in a cell. This triggers all other effects.

Specific actions of the α₁ receptor mainly involves smooth muscle contraction. It causes vasoconstriction in many blood vessels including those of the skin & gastrointestinal system and to kidney (renal artery)^[5] and brain^[6]. Other areas of smooth muscle contraction are:

• ureter
• vas deferens
• hair (erector pili muscles)
• uterus (when pregnant)
• urethral sphincter
• bronchioles (although minor to the relaxing effect of β₂ receptor on bronchioles)
• blood vessels of ciliary body (stimulation causes mydriasis)

Further effects include glycogenolysis and gluconeogenesis from adipose tissue^[7] and liver, as well as secretion from sweat glands^[7] and Na⁺ reabsorption from kidney.^[7]

Antagonists may be used in hypertension.

α₂ receptor

There are 3 highly homologous subtypes of α₂ receptors: α2A, α2Β, and α2C.

Specific actions of the α₂ receptor include:

• inhibition of insulin release in pancreas.^[7]
• induction of glucagon release from pancreas.
• contraction of sphincters of the gastrointestinal tract
• negative feedback in the neuronal synapses
• platelet aggregation

β receptors

β₁ receptor

Specific actions of the β₁ receptor include:

• Increase cardiac output, by raising heart rate (positive chronotropic effect) and increasing impulse conduction and increasing contraction thus increasing the volume expelled with each beat (increased ejection fraction).
• Renin release from juxtaglomerular cells.^[7]
• Lipolysis in adipose tissue.^[7]

β₂ receptor

The 3D crystallographic structure of the β₂-adrenergic receptor has been determined (PDB 2R4R, 2R4S, 2RH1).^[8][9][10]

Specific actions of the β₂ receptor include:

• Smooth muscle relaxation, e.g. in bronchi.^[7]
• Lipolysis in adipose tissue.^[11]
• Anabolism in skeletal muscle.^[12][13]
• Relax non-pregnant uterus
• Relax detrusor urinae muscle‎ of bladder wall
• Dilate arteries to skeletal muscle
• Glycogenolysis and gluconeogenesis
• Contract sphincters of GI tract
• Thickened secretions from salivary glands.^[7]
• Inhibit histamine-release from mast cells
• Increase renin secretion from kidney
• Promotes insulin release from pancreatic beta cells

β₃ receptor

Specific actions of the β₃ receptor include:

• Enhancement of lipolysis in adipose tissue. However, acitvation of Beta-3 receptors often causes tremors, which is the paramount reason that Beta-3 activating pharmacological agents are not utilized as weight loss agents ^Clarify

See also

• Beta adrenergic receptor kinase
• Beta adrenergic receptor kinase-2

References

Further reading

• Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 11". Pharmacology. Elsevier Churchill Livingstone. ISBN 0-443-07145-4. 
• Rang HP, Dale MM, Ritter JM, Flower RJ (2007). "Ch. 11". Rang and Dale's Pharmacology. Elsevier Churchill Livingstone. pp. 169–170. ISBN 0-443-06911-5. 

External links

• The Adrenergic Receptors
• "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1274. 
• Basic Neurochemistry: α- and β-Adrenergic Receptors
• Brief overview of functions of the beta-3 receptor
• Theory of receptor activation
• Desensitization of beta-1-receptors
• UMich Orientation of Proteins in Membranes protein/pdbid-2rh1 - 3D structure of beta-2 adrenergic receptor in membrane