Adrenergic receptor

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β2 adrenoceptor (PDB: 2rh1​) shown binding carazolol (yellow) on its extracellular site. β2 stimulates cells to increase energy production and utilization. The membrane the receptor is bound to in cells is shown with a gray stripe.

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.

Many cells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system (SNS). The SNS is responsible for the fight-or-flight response, which is triggered by experiences such as exercise or fear-causing situations. This response dilates pupils, increases heart rate, mobilizes energy, and diverts blood flow from non-essential organs to skeletal muscle. These effects together tend to increase physical performance momentarily.


By the turn of the 19th century, it was agreed that the stimulation of sympathetic nerves could cause different effects on body tissues, depending on the conditions of stimulation (such as the presence or absence of some toxin). Over the first half of the 20th century, two main proposals were made to explain this phenomenon:

  1. There were (at least) two different types of neurotransmitters released from sympathetic nerve terminals, or
  2. There were (at least) two different types of detector mechanisms for a single neurotransmitter.

The first hypothesis was championed by Walter Bradford Cannon and Arturo Rosenblueth,[1] who interpreted many experiments to then propose that there were two neurotransmitter substances, which they called sympathin E (for 'excitation') and sympathin I (for 'inhibition').

The second hypothesis found support from 1906 to 1913, when Henry Hallett Dale explored the effects of adrenaline (which he called adrenine at the time), injected into animals, on blood pressure. Usually, adrenaline would increase the blood pressure of these animals. Although, if the animal had been exposed to ergotoxine, the blood pressure decreased.[2][3] He proposed that the ergotoxine caused "selective paralysis of motor myoneural junctions" (i.e. those tending to increase the blood pressure) hence revealing that under normal conditions that there was a "mixed response", including a mechanism that would relax smooth muscle and cause a fall in blood pressure. This "mixed response", with the same compound causing either contraction or relaxation, was conceived of as the response of different types of junctions to the same compound.

This line of experiments were developed by several groups, including DT Marsh and colleagues,[4] who in February 1948 showed that a series of compounds structurally related to adrenaline could also show either contracting or relaxing effects, depending on whether or not other toxins were present. This again supported the argument that the muscles had two different mechanisms by which they could respond to the same compound. In June of that year, Raymond Ahlquist, Professor of Pharmacology at Medical College of Georgia, published a paper concerning adrenergic nervous transmission.[5] In it, he explicitly named the different responses as due to what he called α receptors and β receptors, and that the only sympathetic transmitter was adrenaline. While the latter conclusion was subsequently shown to be incorrect (it is now known to be noradrenaline), his receptor nomenclature and concept of two different types of detector mechanisms for a single neurotransmitter, remains. In 1954, he was able to incorporate his findings in a textbook, Drill's Pharmacology in Medicine,[6] and thereby promulgate the role played by α and β receptor sites in the adrenaline/noradrenaline cellular mechanism. These concepts would revolutionise advances in pharmacotherapeutic research, allowing the selective design of specific molecules to target medical ailments rather than rely upon traditional research into the efficacy of pre-existing herbal medicines.


The mechanism of adrenoreceptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenoreceptors. The α1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. The α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. The β receptor couples to Gs and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

The mechanism of adrenoreceptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenoreceptors. The α1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. The α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. The β receptor couples to Gs and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis. There are two main groups of adrenoreceptors, α and β, with 9 subtypes in total:

  • α receptors are subdivided into α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor)[7]
    • α1 has 3 subtypes: α1A, α1B and α1D[a]
    • α2 has 3 subtypes: α2A, α2B and α2C
  • β receptors are subdivided into β1, β2 and β3. All 3 are coupled to Gs proteins, but β2 and β3 also couple to Gi[7]

Gi and Gs are linked to adenylyl cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger (Gi inhibits the production of cAMP) cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding.

Roles in circulation[edit]

Epinephrine (adrenaline) reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated at pharmacologic doses, they override the vasodilation mediated by β-adrenoreceptors because there are more peripheral α1 receptors than β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. However, the opposite is true in the coronary arteries, where β2 response is greater than that of α1, resulting in overall dilation with increased sympathetic stimulation. At lower levels of circulating epinephrine (physiologic epinephrine secretion), β-adrenoreceptor stimulation dominates since epinephrine has a higher affinity for the β2 adrenoreceptor than the α1 adrenoreceptor, producing vasodilation followed by decrease of peripheral vascular resistance.[8]


Smooth muscle behavior is variable depending on anatomical location. Smooth muscle contraction/relaxation is generalized below. One important note is the differential effects of increased cAMP in smooth muscle compared to cardiac muscle. Increased cAMP will promote relaxation in smooth muscle, while promoting increased contractility and pulse rate in cardiac muscle.

Receptor Agonist potency order Agonist action Mechanism Agonists Antagonists
α1: A, B, D[a] Norepinephrine > epinephrine >> isoprenaline[9] Smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucosa and abdominal viscera & sphincter contraction of the GI tract and urinary bladder Gq: phospholipase C (PLC) activated, IP3, and DAG, rise in calcium[7]

(Alpha-1 agonists)

(Alpha-1 blockers)


Antihistamines (H1 antagonists)

α2: A, B, C Epinephrine = norepinephrine >> isoprenaline[9] Smooth muscle mixed effects, norepinephrine (noradrenaline) inhibition, platelet activation Gi: adenylate cyclase inactivated, cAMP down[7]

(Alpha-2 agonists)

(Alpha-2 blockers)
β1 Isoprenaline > epinephrine > norepinephrine[9] Positive chronotropic, dromotropic and inotropic effects, increased amylase secretion Gs: adenylate cyclase activated, cAMP up[7] (β1-adrenergic agonist) (Beta blockers)
β2 Isoprenaline > epinephrine > norepinephrine[9] Smooth muscle relaxation (bronchodilation for example) Gs: adenylate cyclase activated, cAMP up (also Gi, see α2)[7] (β2-adrenergic agonist) (Beta blockers)
β3 Isoprenaline > norepinephrine = epinephrine[9] Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder Gs: adenylate cyclase activated, cAMP up (also Gi, see α2)[7] (β3-adrenergic agonist) (Beta blockers)

α receptors[edit]

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

Subtype unspecific α agonists (see actions above) can be used to treat rhinitis (they decrease mucus secretion). Subtype unspecific α antagonists can be used to treat pheochromocytoma (they decrease vasoconstriction caused by norepinephrine).[7]

α1 receptor[edit]

α1-adrenoreceptors are members of the Gq protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell. This triggers all other effects, including a prominent slow after depolarizing current (sADP) in neurons.[15]

Actions of the α1 receptor mainly involve smooth muscle contraction. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney (renal artery)[16] and brain.[17] Other areas of smooth muscle contraction are:

Actions also include glycogenolysis and gluconeogenesis from adipose tissue and liver; secretion from sweat glands and Na+ reabsorption from kidney.[19]

α1 antagonists can be used to treat:[7]

α2 receptor[edit]

The α2 receptor couples to the Gi/o protein.[20] It is a presynaptic receptor, causing negative feedback on, for example, norepinephrine (NE). When NE is released into the synapse, it feeds back on the α2 receptor, causing less NE release from the presynaptic neuron. This decreases the effect of NE. There are also α2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.

Actions of the α2 receptor include:

α2 agonists (see actions above) can be used to treat:[7]

α2 antagonists can be used to treat:[7]

β receptors[edit]

Subtype unspecific β agonists can be used to treat:[7]

Subtype unspecific β antagonists (beta blockers) can be used to treat:[7]

β1 receptor[edit]

Actions of the β1 receptor include:

β2 receptor[edit]

Actions of the β2 receptor include:

β2 agonists (see actions above) can be used to treat:[7]

β3 receptor[edit]

Actions of the β3 receptor include:

β3 agonists could theoretically be used as weight-loss drugs, but are limited by the side effect of tremors.

See also[edit]


  1. ^ a b There is no α1C receptor. There was a subtype known as C, but it was found to be identical to one of the previously discovered subtypes. To avoid confusion, naming was continued with the letter D. Before June 1995 α1A was named α1C. α1D was named α1A, α1D or α1A/D.[32]


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Further reading[edit]

  • Rang HP, Dale MM, Ritter JM, Flower RJ (2007). "Chapter 11: Noradrenergic transmission". Rang and Dale's Pharmacology (6th ed.). Elsevier Churchill Livingstone. pp. 169–170. ISBN 978-0-443-06911-6.

External links[edit]