Adrenergic receptor

Epinephrine

Norepinephrine

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

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:

1. There were (at least) two different types of neurotransmitter released from sympathetic nerve terminals, or
2. There were (at least) two different types of detector mechanisms for a single neurotransmitter.

The first hypothesis was championed by Walter 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 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 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 dectors 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 adrenergic receptors, α and β, with several subtypes.

• α receptors have the subtypes α₁ (a G_q coupled receptor) and α₂ (a G_i 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 G_s proteins (although β₂ also couples to G_i), 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.

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α₁, α₂ or β-adrenergic receptors. α₁ couples to G_q, which results in increased intracellular Ca²⁺ and subsequent smooth muscle contraction. α₂, on the other hand, couples to G_i, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. β receptors couple to G_s, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

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, 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 agonists) Noradrenaline Phenylephrine Methoxamine Cirazoline Xylometazoline Midodrine Metaraminol Chloroethylclonidine	(Alpha-1 blockers) Acepromazine Alfuzosin Doxazosin Phenoxybenzamine Phentolamine Prazosin Tamsulosin Terazosin Trazodone (TCA:s) Amitriptyline Clomipramine Doxepin Trimipramine Typical and atypical antipsychotics Antihistamines (H1 antagonists) Hydroxyzine
α2: A, B, C	Epinephrine ≥ norepinephrine >> isoprenaline	Smooth muscle mixed effects, norepinephrine (noradrenaline) inhibition, platelet activation	Gi: adenylate cyclase inactivated, cAMP down	(Alpha-2 agonists) Agmatine Dexmedetomidine Medetomidine Romifidine Clonidine Chloroethylclonidine Brimonidine Detomidine Lofexidine Xylazine Tizanidine Guanfacine Amitraz	(Alpha-2 blockers) Phentolamine Yohimbine Idazoxan Atipamezole Trazodone Typical and atypical antipsychotics
β1	Isoprenaline > epinephrine = norepinephrine	Positive Chronotropic, Dromotropic and inotropic effects, increased amylase secretion	Gs: adenylate cyclase activated, cAMP up	(β1-adrenergic agonist) Dobutamine Isoprenaline Noradrenaline	(Beta blockers) Metoprolol Atenolol Bisoprolol Propranolol Timolol Nebivolol Vortioxetine
β2	Isoprenaline > epinephrine >> norepinephrine	Smooth muscle relaxation (Ex. Bronchodilation)	Gs: adenylate cyclase activated, cAMP up (also Gi, see α2)	(β2-adrenergic agonist) Salbutamol (Albuterol in USA) Bitolterol mesylate Formoterol Isoprenaline Levalbuterol Metaproterenol Salmeterol Terbutaline Ritodrine	(Beta blockers) Butoxamine Timolol Propranolol
β3	Isoprenaline = norepinephrine > epinephrine	Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder	Gs: adenylate cyclase activated, cAMP up	(β3-adrenergic agonist) L-796568 Amibegron Solabegron	(Beta blockers) SR 59230A

^†There is no α_1C 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

Main article: Alpha-1 adrenergic receptor

α₁-adrenergic receptors are members of the G_q protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, G_q, 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

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

Main article: Alpha-2 adrenergic receptor

The α₂ receptor couples to the G_i/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.

There are 3 highly homologous subtypes of α₂ receptors: α_2A, α_2Β, and α_2C.

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 norepinephrine (NE) release in CNS
• increased thrombocyte aggregation

β receptors

β₁ receptor

Main article: Beta-1 adrenergic 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.

β₂ receptor

Main article: Beta-2 adrenergic receptor

Beta-2 adrenergic receptor (PDB: 2rh1​), which stimulates cells to increase energy production and utilization. The membrane is shown schematically with a gray stripe.

Specific actions of the β₂ receptor include the following:

• Smooth muscle relaxation, e.g. in bronchi, GI tract (decreased motility), vasodilation of blood vessels, especially those to skeletal muscle (in contrast to vasoconstriction caused by alpha₁ and alpha₂ adrenoceptors, which is usually the dominant effect).
• 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
• Stimulates 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

Main article: Beta-3 adrenergic 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

External links

• Alpha receptors illustrated
• The Adrenergic Receptors
• 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