Adrenergic receptor

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 skeletal muscle.


  • History 1
  • Categories 2
    • Roles in circulation 2.1
    • Subtypes 2.2
    • α receptors 2.3
      • α1 receptor 2.3.1
      • α2 receptor 2.3.2
    • β receptors 2.4
      • β1 receptor 2.4.1
      • β2 receptor 2.4.2
      • β3 receptor 2.4.3
  • See also 3
  • References 4
  • Further reading 5
  • External links 6


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,

  • Alpha receptors illustrated
  • The Adrenergic Receptors
  • "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
  • Basic Neurochemistry: α- and β-Adrenergic Receptors
  • receptor3Brief overview of functions of the β
  • Theory of receptor activation
  • receptors1Desensitization of β
  • UMich Orientation of Proteins in Membranes protein/pdbid-2rh1 - 3D structure of β2 adrenergic receptor in membrane

External links

  • Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Chapter 11: Noradrenergic transmission". Pharmacology (5th ed.). Elsevier Churchill Livingstone.  
  • 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.  

Further reading

  1. ^ Cannon, W. B.; Rosenblueth, A. (31 May 1933). "Studies On Conditions Of Activity In Endocrine Organs". American Journal of Physiology 104 (3): 557–574. 
  2. ^ Dale, H.H. (1906). "On some physiological actions of ergot". Journal of Physiology 34: 163–206. 
  3. ^ Dale, H.H. (1913). "On the action of ergotoxine; with special reference to the existence of sympathetic vasodilators". pp. 291–300.  
  5. ^ Ahlquist, R.P. (1948). "A study of the adrenotropic receptors". Americal Journal of Physiology 153: 586–600. Retrieved 21 August 2015. 
  6. ^ Drill, Victor Alexander (1954). Pharmacology in medicine: a collaborative textbook. New York: McGraw-Hill. 
  7. ^ a b Kou Qin, Pooja R. Sethi and Nevin A. Lambert (August 2008). "Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins". The FASEB Journal 22 (8): 2920–2927.  
  8. ^ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (November 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophys. J. 79 (5): 2547–56.  
  9. ^ Nisoli E, Tonello C, Landi M, Carruba MO (1996). -adrenergic receptor antagonist SR 59230A in rat brown adipocytes"3"Functional studies of the first selective β. Mol. Pharmacol. 49 (1): 7–14.  
  10. ^ english
  11. ^ Elliott J (1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both α1- and α2-receptors mediating vasoconstriction". J. Vet. Pharmacol. Ther. 20 (4): 308–17.  
  12. ^ Sagrada A, Fargeas MJ, Bueno L (1987). adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat"2 and α1"Involvement of α. Gut 28 (8): 955–9.  
  13. ^ Smith, Richard; Weitz, Jeffery; Araneda, Ricardo (2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology 102 (2): 1103–1114.  
  14. ^ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (1981). adrenergic receptors: biochemical and pharmacological correlations"2 and α1"Renal α. J. Pharmacol. Exp. Ther. 219 (2): 400–6.  
  15. ^ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
  16. ^ Moro, C; Tajouri, L; Chess-Williams, R (January 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7.  
  17. ^ a b c d e f Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer.  
  18. ^ Zhao, T. J.; Sakata, I.; Li, R. L.; Liang, G.; Richardson, J. A.; Brown, M. S.; et al. (2010). "Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice". Proc Natl Acad Sci U S A 107 (36): 15868–15873.  
  19. ^ "Adrenergic and Cholinergic Receptors in Blood Vessels". Cardiovascular Physiology. Retrieved 5 May 2015. 
  20. ^ Large V; Hellström L; Reynisdottir S; et al. (December 1997). "Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function". J. Clin. Invest. 100 (12): 3005–13.  
  21. ^ Kline WO, Panaro FJ, Yang H, Bodine SC (February 2007). "Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol". J. Appl. Physiol. 102 (2): 740–7.  
  22. ^ Kamalakkannan G; Petrilli CM; George I; et al. (April 2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". J. Heart Lung Transplant. 27 (4): 457–61.  
  23. ^ Elenkov; I. J.; R. L. Wilder; et al. (2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacol Rev 52 (4): 595–638.  


See also

  • Enhancement of lipolysis in adipose tissue. β3 activating drugs could theoretically be used as weight-loss agents, but are limited by the side effect of tremors.

Specific actions of the β3 receptor include:

β3 receptor

Specific actions of the β2 receptor include the following:

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

β2 receptor

  • Increase cardiac output by increasing heart rate (positive chronotropic effect), conduction velocity (positive dromotropic effect), and stroke volume (by enhancing contractility—positive inotropic effect).
  • Increase renin secretion from juxtaglomerular cells of the kidney.
  • Increase ghrelin secretion from the stomach.[18]

Specific actions of the β1 receptor include:

β1 receptor

β receptors

  • inhibition of insulin release in the pancreas.[17]
  • induction of glucagon release from the pancreas.
  • contraction of sphincters of the gastrointestinal tract
  • negative feedback in the neuronal synapses - presynaptic inhibition of noradrenalin (NA) release in CNS
  • increased thrombocyte aggregation

Specific actions of the α2 receptor include:

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

The α2 receptor couples to the Gi/o protein.[7] It is a presynaptic receptor, causing negative feedback on, for example, norepinephrine. When NA is released into the synapse, it feeds back on the α2 receptor, causing less NA release from the presynaptic neuron. This decreases the effect of NA. There are also α2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.

α2 receptor

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

Further effects include glycogenolysis and gluconeogenesis from adipose tissue[17] and liver, as well as secretion from sweat glands[17] and Na+ reabsorption from kidney.[17]

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)[14] and brain.[15] Other areas of smooth muscle contraction are:

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 [13]

α1 receptor

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

α receptors

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.

Receptor Agonist potency order Selected action
of agonist
Mechanism Agonists Antagonists
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)

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 (β3-adrenergic agonist) (Beta blockers)

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.


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.

Roles in circulation

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.
  • α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor[7]). Phenylephrine is a selective agonist of the α receptor.
  • β receptors have the subtypes β1, β2 and β3. All three are linked to Gs proteins (although β2 also couples to Gi),[8] 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 non-selective agonist.

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


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. [6],Drill's Pharmacology in Medicine, remains. In 1954, he was able to incorporate his findings in a textbook, two different types of dectors mechanisms for a single neurotransmitter 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 [5]