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 pupil, increasing heart rate, mobilizing energy, and diverting blood flow from non-essential organs to skeletal muscle.

History

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.

Categories

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 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. 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.

Subtypes

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)

(TCA:s)

Antihistamines (H1 antagonists)

α2: A, B, C Epinephrine = norepinephrine >> isoprenaline (however do consider that a bit of Norepinephrine was already used in a1, thus giving Epinephrine a relatively stronger affinity in a2) 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)

†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, α2Β, 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

References

  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. PMC 1465771 Freely accessible. PMID 16992821. doi:10.1113/jphysiol.1906.sp001148.
  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. PMC 1420444 Freely accessible. PMID 16993202. doi:10.1113/jphysiol.1913.sp001592.
  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.
  5. ↑ Ahlquist RP (Jun 1948). "A study of the adrenotropic receptors". The American Journal of Physiology. 153 (3): 586–600. PMID 18882199.
  6. ↑ Drill VA (1954). Pharmacology in medicine: a collaborative textbook. New York: McGraw-Hill.
  7. 1 2 Qin K, Sethi PR, Lambert NA (Aug 2008). "Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins". FASEB Journal. 22 (8): 2920–7. PMC 2493464 Freely accessible. PMID 18434433. doi:10.1096/fj.08-105775.
  8. ↑ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (Nov 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophysical Journal. 79 (5): 2547–56. Bibcode:2000BpJ....79.2547C. PMC 1301137 Freely accessible. PMID 11053129. doi:10.1016/S0006-3495(00)76495-2.
  9. ↑ Nisoli E, Tonello C, Landi M, Carruba MO (Jan 1996). "Functional studies of the first selective beta 3-adrenergic receptor antagonist SR 59230A in rat brown adipocytes". Molecular Pharmacology. 49 (1): 7–14. PMID 8569714.
  10. ↑ Elliott J (Aug 1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction". Journal of Veterinary Pharmacology and Therapeutics. 20 (4): 308–17. PMID 9280371. doi:10.1046/j.1365-2885.1997.00078.x.
  11. ↑ Sagrada A, Fargeas MJ, Bueno L (Aug 1987). "Involvement of alpha-1 and alpha-2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat". Gut. 28 (8): 955–9. PMC 1433140 Freely accessible. PMID 2889649. doi:10.1136/gut.28.8.955.
  12. ↑ Smith RS, Weitz CJ, Araneda RC (Aug 2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology. 102 (2): 1103–14. PMC 2724365 Freely accessible. PMID 19474170. doi:10.1152/jn.91093.2008.
  13. ↑ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (Nov 1981). "Renal alpha-1 and alpha-2 adrenergic receptors: biochemical and pharmacological correlations". The Journal of Pharmacology and Experimental Therapeutics. 219 (2): 400–6. PMID 6270306.
  14. ↑ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
  15. ↑ Moro C, Tajouri L, Chess-Williams R (Jan 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7. PMID 23200975. doi:10.1016/j.urology.2012.09.011.
  16. 1 2 3 4 5 6 Fitzpatrick D, Purves D, Augustine G (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
  17. ↑ Zhao TJ, Sakata I, Li RL, Liang G, Richardson JA, Brown MS, et al. (Sep 2010). "Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice". Proceedings of the National Academy of Sciences of the United States of America. 107 (36): 15868–73. Bibcode:2010PNAS..10715868Z. PMC 2936616 Freely accessible. PMID 20713709. doi:10.1073/pnas.1011116107.
  18. ↑ Liszewski, Kathy (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News (paper). 35 (17): 16.(subscription required)
  19. ↑ "Adrenergic and Cholinergic Receptors in Blood Vessels". Cardiovascular Physiology. Retrieved 5 May 2015.
  20. ↑ Large V, Hellström L, Reynisdottir S, et al. (Dec 1997). "Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function". The Journal of Clinical Investigation. 100 (12): 3005–13. PMC 508512 Freely accessible. PMID 9399946. doi:10.1172/JCI119854.
  21. ↑ Kline WO, Panaro FJ, Yang H, Bodine SC (Feb 2007). "Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol". Journal of Applied Physiology. 102 (2): 740–7. PMID 17068216. doi:10.1152/japplphysiol.00873.2006.
  22. ↑ Kamalakkannan G, Petrilli CM, George I, et al. (Apr 2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". The Journal of Heart and Lung Transplantation. 27 (4): 457–61. PMID 18374884. doi:10.1016/j.healun.2008.01.013.
  23. ↑ Santulli, G.; Lombardi, A.; Sorriento, D.; Anastasio, A.; Del Giudice, C.; Formisano, P.; Beguinot, F.; Trimarco, B.; Miele, C.; Iaccarino, G. (2012). "Age-Related Impairment in Insulin Release: The Essential Role of 2-Adrenergic Receptor". Diabetes. 61 (3): 692–701. ISSN 0012-1797. PMC 3282797 Freely accessible. PMID 22315324. doi:10.2337/db11-1027.
  24. ↑ Kim, Soo Mi; Briggs, Josephine P.; Schnermann, Jurgen (2011). "Convergence of major physiological stimuli for renin release on the Gs-alpha/cyclic adenosine monophosphate signaling pathway". Clinical and Experimental Nephrology. 16 (1): 17–24. ISSN 1342-1751. doi:10.1007/s10157-011-0494-1.
  25. ↑ Elenkov IJ, Wilder RL, Chrousos GP, et al. (Dec 2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacological Reviews. 52 (4): 595–638. PMID 11121511.

Further reading

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