Adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine and epinephrine produced by the body, but also many medications like beta blockers, β2 agonists and α2 agonists, which are used to treat high blood pressure and asthma, for example.
Many cells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. 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
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. Over the first half of the 20th century, two main proposals were made to explain this phenomenon:- There were two different types of neurotransmitters released from sympathetic nerve terminals, or
- There were two different types of detector mechanisms for a single neurotransmitter.
The second hypothesis found support from 1906 to 1913, when Henry Hallett Dale explored the effects of adrenaline, 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. He proposed that the ergotoxine caused "selective paralysis of motor myoneural junctions" 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, 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. 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, 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, 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 adrenoreceptors, α and β, with 9 subtypes in total:- α are divided to α1 and α2
- *α1 has 3 subtypes: α1A, α1B and α1D
- *α2 has 3 subtypes: α2A, α2B and α2C
- β are divided to β1, β2 and β3. All 3 are coupled to Gs proteins, but β2 and β3 also couple to Gi
Roles in circulation
Epinephrine 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. However, the opposite is true in the coronary arteries, where β2 response is greater than that of α1, resulting in overall dilation with increased sympathetic stimulation. At lower levels of circulating epinephrine, 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 | Agonist action | 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 activated, IP3, and DAG, rise in calcium | '
| '
|
| α2: A, B, C | Epinephrine = norepinephrine >> isoprenaline | Smooth muscle mixed effects, norepinephrine inhibition, platelet activation | Gi: adenylate cyclase inactivated, cAMP down | '
| ' |
| β1 | Isoprenaline > norepinephrine > epinephrine | Positive chronotropic, dromotropic and inotropic effects, increased amylase secretion | Gs: adenylate cyclase activated, cAMP up | ' | ' |
| β2 | Isoprenaline > epinephrine > norepinephrine | Smooth muscle relaxation | Gs: adenylate cyclase activated, cAMP up | ' | ' |
| β3 | Isoprenaline > norepinephrine = epinephrine | Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder | Gs: adenylate cyclase activated, cAMP up | ' |
α receptors
α receptors have actions in common, but also individual effects. Common actions include:- vasoconstriction
- decreased motility of smooth muscle in gastrointestinal tract
α1 receptor
α1-adrenoreceptors are members of the Gq protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C. The PLC cleaves phosphatidylinositol 4,5-bisphosphate, which in turn causes an increase in inositol triphosphate and diacylglycerol. 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 in neurons.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 and brain. Other areas of smooth muscle contraction are:
- ureter
- vas deferens
- hair
- uterus
- urethral sphincter
- urothelium and lamina propria
- bronchioles
- blood vessels of ciliary body
α1 antagonists can be used to treat:
- hypertension – decrease blood pressure by decreasing peripheral vasoconstriction
- benign prostate hyperplasia – relax smooth muscles within the prostate thus easing urination
α2 receptor
Actions of the α2 receptor include:
- decreased insulin release from the pancreas
- increased glucagon release from the pancreas
- contraction of sphincters of the GI-tract
- negative feedback in the neuronal synapses - presynaptic inhibition of norepinephrine release in CNS
- increased platelet aggregation
- decreases peripheral vascular resistance
- hypertension – decrease blood pressure raising actions of the sympathetic nervous system
- impotence – relax penile smooth muscles and ease blood flow
- depression – enhance mood by increasing norepinephrine secretion
β receptors
- heart failure – increase cardiac output acutely in an emergency
- circulatory shock – increase cardiac output thus redistributing blood volume
- anaphylaxis – bronchodilation
- heart arrhythmia – decrease the output of sinus node thus stabilizing heart function
- coronary artery disease – reduce heart rate and hence increasing oxygen supply
- heart failure – prevent sudden death related to this condition, which is often caused by ischemias or arrhythmias
- hyperthyroidism – reduce peripheral sympathetic hyper-responsiveness
- migraine – reduce number of attacks
- stage fright – reduce tachycardia and tremor
- glaucoma – reduce intraocular pressure
β1 receptor
- increase cardiac output by increasing heart rate, conduction velocity, stroke volume, and rate of relaxation of the myocardium, by increasing calcium ion sequestration rate, which aids in increasing heart rate
- increase renin secretion from juxtaglomerular cells of the kidney
- increase renin secretion from kidney
- increase ghrelin secretion from the stomach
β2 receptor
- smooth muscle relaxation throughout many areas of the body, e.g. in bronchi, GI tract, veins, especially those to skeletal muscle
- lipolysis in adipose tissue
- anabolism in skeletal muscle
- uptake of potassium into cells
- relax non-pregnant uterus
- relax detrusor urinae muscle of bladder wall
- dilate arteries to skeletal muscle
- glycogenolysis and gluconeogenesis
- stimulates insulin secretion
- contract sphincters of GI tract
- thickened secretions from salivary glands
- inhibit histamine-release from mast cells
- involved in brain - immune communication
- asthma and COPD – reduce bronchial smooth muscle contraction thus dilating the bronchus
- hyperkalemia – increase cellular potassium intake
- preterm birth – reduce uterine smooth muscle contractions
β3 receptor
- increase of lipolysis in adipose tissue
- relax the bladder