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Beta-adrenergic receptor

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Beta-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 widening the pupils of the eye, mobilizing energy, and diverting blood flow from non-essential organs to skeletal muscle.

History

Raymond Ahlquist, Professor of Pharmacology at Medical College of Georgia, published a paper concerning adrenergic nervous transmission in 1948[1] but its significance was largely ignored at that time. However, in 1954 he was able to incorporate his findings in a textbook, Drill's Pharmacology in Medicine, and thereby firmly establish the essential role played by α and β receptor sites in the adrenaline/nor-adrenaline cellular mechanism. His discovery 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.

  • α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor). 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),[2] 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.


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.

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, muscosa 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
Epinephrinenorepinephrine >> isoprenaline Smooth muscle mixed effects, norepinephrine (noradrenaline) inhibition, Cardiac muscle relaxation and 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 (Beta blockers)
β2 Isoprenaline > epinephrine >> norepinephrine Smooth muscle relaxation (Ex. Bronchodilation) Gs: adenylate cyclase activated, cAMP up (also Gi, see α2) (Short/long) (Beta blockers)
β3 Isoprenaline = norepinephrine > epinephrine Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder Gs: adenylate cyclase activated, cAMP up
[4]

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.

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)[8] and brain.[9] Other areas of smooth muscle contraction are:

Further effects include glycogenolysis and gluconeogenesis from adipose tissue[11] and liver, as well as secretion from sweat glands[11] and Na+ reabsorption from kidney.[11]

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

α2 receptor

The α2 receptor 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 3 highly homologous subtypes of α2 receptors: α2A, α, and α2C.

Specific actions of the α2 receptor include:

  • inhibition of insulin release in the pancreas.[11]
  • 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

β receptors

β1 receptor

Specific actions of the β1 receptor include:

  • 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.[12]

β2 receptor

Specific actions of the β2 receptor include the following:

β3 receptor

Specific actions of the β3 receptor include:

  • 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.

See also

References

Further reading

External links

  • Alpha receptors illustrated
  • The Adrenergic Receptors
  • Basic Neurochemistry: α- and β-Adrenergic Receptors
  • receptor
  • Theory of receptor activation
  • receptors
  • protein/pdbid-2rh1 - 3D structure of β2 adrenergic receptor in membrane
pt:Receptores adrenérgicos
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