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 (β2) agonists and alpha-2 (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 (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.
Main article: History of catecholamine research
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:
The first hypothesis was championed by Walter Bradford Cannon and Arturo Rosenblueth, 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. 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, 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 (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, 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.
There are two main groups of adrenoreceptors, α and β, with 9 subtypes in total:
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.
Epinephrine (adrenaline) 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 (physiologic epinephrine secretion), 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.
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[a]||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 (PLC) activated, IP3, and DAG, rise in calcium||(Alpha-1 blockers)
Antihistamines (H1 antagonists)
|α2: A, B, C||Epinephrine = norepinephrine >> isoprenaline||Smooth muscle mixed effects, norepinephrine (noradrenaline) inhibition, platelet activation||Gi: adenylate cyclase inactivated, cAMP down||(Alpha-2 blockers)|
|β1||Isoprenaline > norepinephrine > epinephrine||Positive chronotropic, dromotropic and inotropic effects, increased amylase secretion||Gs: adenylate cyclase activated, cAMP up||(β1-adrenergic agonist)||(Beta blockers)|
|β2||Isoprenaline > epinephrine > norepinephrine||Smooth muscle relaxation (bronchodilation for example)||Gs: adenylate cyclase activated, cAMP up (also Gi, see α2)||(β2-adrenergic agonist)||(Beta blockers)|
|β3||Isoprenaline > norepinephrine = epinephrine||Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder||Gs: adenylate cyclase activated, cAMP up (also Gi, see α2)||(β3-adrenergic agonist)||(Beta blockers)|
α receptors have actions in common, but also individual effects. Common (or still receptor unspecified) actions include:
Subtype unspecific α agonists (see actions above) can be used to treat rhinitis (they decrease mucus secretion). Subtype unspecific α antagonists can be used to treat pheochromocytoma (they decrease vasoconstriction caused by norepinephrine).
Main article: Alpha-1 adrenergic receptor
α1-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.
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:
Actions also include glycogenolysis and gluconeogenesis from adipose tissue and liver; secretion from sweat glands and Na+ reabsorption from kidney.
α1 antagonists can be used to treat:
Main article: Alpha-2 adrenergic receptor
The α2 receptor couples to the Gi/o protein. 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 α2 receptor, causing less NE release from the presynaptic neuron. This decreases the effect of NE. There are also α2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.
Actions of the α2 receptor include:
α2 agonists (see actions above) can be used to treat:
α2 antagonists can be used to treat:
Subtype unspecific β agonists can be used to treat:
Subtype unspecific β antagonists (beta blockers) can be used to treat:
Main article: Beta-1 adrenergic receptor
Actions of the β1 receptor include:
Main article: Beta-2 adrenergic receptor
Actions of the β2 receptor include:
β2 agonists (see actions above) can be used to treat:
Main article: Beta-3 adrenergic receptor
Actions of the β3 receptor include:
β3 agonists could theoretically be used as weight-loss drugs, but are limited by the side effect of tremors.