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Adrenergic receptor - Wikipedia
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Adrenergic receptor

(Redirected from Beta receptors)

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 (βべーた2) agonists and alpha-2 (αあるふぁ2) agonists, which are used to treat high blood pressure and asthma, for example.

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

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.

History

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Main article: History of catecholamine research
 
Epinephrine
 
Norepinephrine

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あるふぁ receptors and βべーた 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あるふぁ and βべーた 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

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The mechanism of adrenoreceptors. Adrenaline or noradrenaline are receptor ligands to either αあるふぁ1, αあるふぁ2 or βべーた-adrenoreceptors. The αあるふぁ1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. The αあるふぁ2, 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べーた 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 αあるふぁ1, αあるふぁ2 or βべーた-adrenoreceptors. The αあるふぁ1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. The αあるふぁ2, 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べーた 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あるふぁ and βべーた, with 9 subtypes in total:

  • αあるふぁ receptors are subdivided into αあるふぁ1 (a Gq coupled receptor) and αあるふぁ2 (a Gi coupled receptor)[7]
    • αあるふぁ1 has 3 subtypes: αあるふぁ1A, αあるふぁ1B and αあるふぁ1D[a]
    • αあるふぁ2 has 3 subtypes: αあるふぁ2A, αあるふぁ2B and αあるふぁ2C
  • βべーた receptors are subdivided into βべーた1, βべーた2 and βべーた3. All 3 are coupled to Gs proteins, but βべーた2 and βべーた3 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

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Epinephrine (adrenaline) reacts with both αあるふぁ- and βべーた-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although αあるふぁ receptors are less sensitive to epinephrine, when activated at pharmacologic doses, they override the vasodilation mediated by βべーた-adrenoreceptors because there are more peripheral αあるふぁ1 receptors than βべーた-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. However, the opposite is true in the coronary arteries, where βべーた2 response is greater than that of αあるふぁ1, resulting in overall dilation with increased sympathetic stimulation. At lower levels of circulating epinephrine (physiologic epinephrine secretion), βべーた-adrenoreceptor stimulation dominates since epinephrine has a higher affinity for the βべーた2 adrenoreceptor than the αあるふぁ1 adrenoreceptor, producing vasodilation followed by decrease of peripheral vascular resistance.[8]

Subtypes

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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
αあるふぁ1: 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)

(TCAs)

Antihistamines (H1 antagonists)

αあるふぁ2: 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)
βべーた1 Isoprenaline > epinephrine > norepinephrine[9] Positive chronotropic, dromotropic and inotropic effects, increased amylase secretion Gs: adenylate cyclase activated, cAMP up[7] (βべーた1-adrenergic agonist) (Beta blockers)
βべーた2 Isoprenaline > epinephrine > norepinephrine[9] Smooth muscle relaxation (bronchodilation for example) Gs: adenylate cyclase activated, cAMP up (also Gi, see αあるふぁ2)[7] (βべーた2-adrenergic agonist) (Beta blockers)
βべーた3 Isoprenaline > norepinephrine = epinephrine[9] Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder Gs: adenylate cyclase activated, cAMP up (also Gi, see αあるふぁ2)[7] (βべーた3-adrenergic agonist) (Beta blockers)

αあるふぁ receptors

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

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

αあるふぁ1 receptor

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Main article: Alpha-1 adrenergic receptor

αあるふぁ1-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 αあるふぁ1 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]

αあるふぁ1 antagonists can be used to treat:[7]

αあるふぁ2 receptor

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Main article: Alpha-2 adrenergic receptor

The αあるふぁ2 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 αあるふぁ2 receptor, causing less NE release from the presynaptic neuron. This decreases the effect of NE. There are also αあるふぁ2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.

Actions of the αあるふぁ2 receptor include:

αあるふぁ2 agonists (see actions above) can be used to treat:[7]

αあるふぁ2 antagonists can be used to treat:[7]

βべーた receptors

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

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

βべーた1 receptor

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Main article: Beta-1 adrenergic receptor

Actions of the βべーた1 receptor include:

βべーた2 receptor

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Main article: Beta-2 adrenergic receptor

Actions of the βべーた2 receptor include:

βべーた2 agonists (see actions above) can be used to treat:[7]

βべーた3 receptor

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Main article: Beta-3 adrenergic receptor

Actions of the βべーた3 receptor include:

βべーた3 agonists could theoretically be used as weight-loss drugs, but are limited by the side effect of tremors.

See also

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Notes

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  1. ^ a b There is no αあるふぁ1C 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 αあるふぁ1A was named αあるふぁ1C. αあるふぁ1D was named αあるふぁ1A, αあるふぁ1D or αあるふぁ1A/D.[32]

References

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  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. doi:10.1152/ajplegacy.1933.104.3.557.
  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 1465771. 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 1420444. 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.
  5. ^ Ahlquist RP (Jun 1948). "A study of the adrenotropic receptors". The American Journal of Physiology. 153 (3): 586–600. doi:10.1152/ajplegacy.1948.153.3.586. PMID 18882199. S2CID 1518772.
  6. ^ Drill VA (1954). Pharmacology in medicine: a collaborative textbook. New York: McGraw-Hill.
  7. ^ a b c d e f g h i j k l m n o Perez, Dianne M. (2006). The adrenergic receptors in the 21st century. Totowa, New Jersey: Humana Press. pp. 54, 129–134. ISBN 978-1588294234. LCCN 2005008529. OCLC 58729119.
  8. ^ Zwieten, Van; A, P. (1986). "Interaction Between αあるふぁ and βべーた-Adrenoceptor-Mediated Cardiovascular Effects". Journal of Cardiovascular Pharmacology. 8: S21-8. doi:10.1097/00005344-198608004-00004. ISSN 0160-2446. PMID 2427848.
  9. ^ a b c d e Rang HP, Ritter JM, Flower RJ, Henderson G (2016). Rang and Dale's pharmacology (8th ed.). United Kingdom: Elsevier. p. 179. ISBN 9780702053627. OCLC 903083639.
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  13. ^ Elliott J (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. doi:10.1046/j.1365-2885.1997.00078.x. PMID 9280371.
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  15. ^ 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. doi:10.1152/jn.91093.2008. PMC 2724365. PMID 19474170.
  16. ^ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (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.
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  18. ^ Moro C, Tajouri L, Chess-Williams R (2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7. doi:10.1016/j.urology.2012.09.011. PMID 23200975.
  19. ^ a b c d Fitzpatrick D, Purves D, Augustine G (2004). "Table 20:2". Neuroscience (3rd ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
  20. ^ Qin K, Sethi PR, Lambert NA (2008). "Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins". FASEB Journal. 22 (8): 2920–7. doi:10.1096/fj.08-105775. PMC 2493464. PMID 18434433.
  21. ^ Ørn S, Dickstein K (2002-04-01). "How do heart failure patients die?". European Heart Journal Supplements. 4 (Suppl D): D59–D65. doi:10.1093/oxfordjournals.ehjsupp.a000770.
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  26. ^ Kline WO, Panaro FJ, Yang H, Bodine SC (2007). "Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol". Journal of Applied Physiology. 102 (2): 740–7. doi:10.1152/japplphysiol.00873.2006. PMID 17068216. S2CID 14292004.
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  32. ^ Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ, Minneman KP, Ruffolo RR (June 1995). "International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1-adrenoceptors: consensus update". Pharmacological Reviews. 47 (2): 267–70. PMID 7568329.

Further reading

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  • 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.
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