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 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), 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.
†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:
- Vasoconstriction of veins
- Decrease motility of smooth muscle in gastrointestinal tract
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) and brain. Other areas of smooth muscle contraction are:
- ureter
- vas deferens
- hair (arrector pili muscles)
- uterus (when pregnant)
- urethral sphincter
- urothelium and lamina propria
- bronchioles (although minor due to the relaxing effect of β2 receptor on bronchioles)
- blood vessels of ciliary body (stimulation causes mydriasis)
Further effects include glycogenolysis and gluconeogenesis from adipose tissue and liver, as well as secretion from sweat glands and Na+ reabsorption from kidney.
Antagonists may be used primarily in hypertension, anxiety disorder, and panic attacks.
α2 receptor
The α2 receptor couples to the Gi/o protein. 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.
There are 3 highly homologous subtypes of α2 receptors: α2A, α2Î', and α2C.
Specific actions of the α2 receptor include:
- inhibition of insulin release in the pancreas.
- 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 contractilityâ€"positive inotropic effect).
- Increase renin secretion from juxtaglomerular cells of the kidney.
- Increase ghrelin secretion from the stomach.
β2 receptor
Specific actions of the β2 receptor include the following:
- Smooth muscle relaxation, e.g. in bronchi, GI tract (decreased motility).
- Lipolysis in adipose tissue.
- Anabolism in skeletal muscle.
- Relax non-pregnant uterus
- Relax detrusor urinae muscle of bladder wall
- Dilate arteries to skeletal muscle
- Glycogenolysis and gluconeogenesis
- Inhibits insulin secretion
- Contract sphincters of GI tract
- Thickened secretions from salivary glands.
- Inhibit histamine-release from mast cells
- Increase renin secretion from kidney
- Relaxation of Bronchioles (salbutamol, a β2 agonist relieves bronchiole constriction)
- Involved in brain - immune communication
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
- Beta adrenergic receptor kinase
- Beta adrenergic receptor kinase-2
References
Further reading
- Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Chapter 11: Noradrenergic transmission". Pharmacology (5th ed.). Elsevier Churchill Livingstone. ISBNÂ 0-443-07145-4.Â
- Rang HP, Dale MM, Ritter JM, Flower RJ (2007). "Chapter 11: Noradrenergic transmission". Rang and Dale's Pharmacology (6th ed.). Elsevier Churchill Livingstone. pp. 169â€"170. ISBN 0-443-06911-5.Â
External links
- Alpha receptors illustrated
- The Adrenergic Receptors
- "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.Â
- Basic Neurochemistry: α- and β-Adrenergic Receptors
- Brief overview of functions of the β3 receptor
- Theory of receptor activation
- Desensitization of β1 receptors
- UMich Orientation of Proteins in Membranes protein/pdbid-2rh1 - 3D structure of β2 adrenergic receptor in membrane