Adrenergic receptor

The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline).

Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. The sympathetic nervous system is responsible for the fight-or-flight response, which includes dilating the pupils, increasing heart rate, mobilizing energy, and diverting blood flow from non-essential organs to skeletal muscle.


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 neurotransmitter 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 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 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 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 dectors 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.


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

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenergic receptors. α1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. 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. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

Roles in circulation

Epinephrine (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 because there are more peripheral α1 receptors than β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, producing vasodilation followed by decrease of peripheral vascular resistance.


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 Selected action of agonist Mechanism Agonists Antagonists
α1: A, B, D Norepinephrine > epinephrine >> isoprenaline 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

(Alpha-1 agonists)

(Alpha-1 blockers)


Antihistamines (H1 antagonists)

α2: A, B, C Epinephrinenorepinephrine >> isoprenaline Smooth muscle mixed effects, norepinephrine (noradrenaline) inhibition, platelet activation Gi: adenylate cyclase inactivated, cAMP down

(Alpha-2 agonists)

(Alpha-2 blockers)
β1 Isoprenaline > epinephrine = norepinephrine Positive Chronotropic, Dromotropic and inotropic effects, increased amylase secretion Gs: adenylate cyclase activated, cAMP up (β1-adrenergic agonist) (Beta blockers)
β2 Isoprenaline > epinephrine >> norepinephrine Smooth muscle relaxation (Ex. Bronchodilation) Gs: adenylate cyclase activated, cAMP up (also Gi, see α2) (β2-adrenergic agonist) (Beta blockers)
β3 Isoprenaline = norepinephrine > epinephrine Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder Gs: adenylate cyclase activated, cAMP up 3-adrenergic agonist) (Beta blockers)

There is no α1C 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:

α1 receptor

α1-adrenergic receptors 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 [12]

Specific 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)[13] and brain.[14] Other areas of smooth muscle contraction are:

Further effects include glycogenolysis and gluconeogenesis from adipose tissue[16] and liver, as well as secretion from sweat glands[16] and Na+ reabsorption from kidney.[16]

Antagonists may be used primarily in hypertension, anxiety disorder, and panic attacks.

α2 receptor

The α2 receptor couples to the Gi/o protein.[7] 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.

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

Specific actions of the α2 receptor include:

β receptors

β1 receptor

Specific actions of the β1 receptor include:

β2 receptor

The β2 receptor "binds epinephrine and is involved in the fight or flight response".[18]

Beta-2 adrenergic receptor (PDB: 2rh1), which stimulates cells to increase energy production and utilization. The membrane is shown schematically with a gray stripe.

Specific actions of the β2 receptor include the following:

β3 receptor

Specific actions of the β3 receptor include:

See also


  1. Cannon WB, Rosenbluth A (31 May 1933). "Studies On Conditions Of Activity In Endocrine Organs XXVI: Sympathin E and Sympathin I". American Journal of Physiology. 104 (3): 557–574.
  2. Dale HH (May 1906). "On some physiological actions of ergot". The Journal of Physiology. 34 (3): 163–206. doi:10.1113/jphysiol.1906.sp001148. PMC 1465771Freely accessible. PMID 16992821.
  3. Dale HH (Jun 1913). "On the action of ergotoxine; with special reference to the existence of sympathetic vasodilators". The Journal of Physiology. 46 (3): 291–300. doi:10.1113/jphysiol.1913.sp001592. PMC 1420444Freely accessible. PMID 16993202.
  4. Marsh DT, Pelletier MH, Rose CA (Feb 1948). "The comparative pharmacology of the N-alkyl-arterenols". The Journal of Pharmacology and Experimental Therapeutics. 92 (2): 108–20. PMID 18903395.
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Further reading

External links

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