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, beta-2 agonists and alpha-2 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 end 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. In 1967, Lands et el. had published the classification of the adrenergic receptors as classified into two subtypes, which were the β1 and β2 adrenergic receptors.
Categories
The mechanism of adrenoreceptors
Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenoreceptors. The α1 couples to Gq, which results in increased intracellular Ca2+ and subsequent smooth muscle contraction. The 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. The β 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 and β, with 9 subtypes in total:
- α receptors are subdivided into α1 and α2
- * α1 has 3 subtypes: α1A, α1B and α1D
- * α2 has 3 subtypes: α2A, α2B and α2C
- β receptors are subdivided into 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 > epinephrine > norepinephrine | 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 flow 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 trisphosphate 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 and
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