β2 adrenoceptor (PDB:2rh1) shown bindingcarazolol (yellow) on itsextracellular site. β2 stimulates cells to increase energy production and utilization. The membrane the receptor is bound to in cells is shown with a gray stripe.
Manycells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate thesympathetic nervous system (SNS). The SNS is responsible for thefight-or-flight response, which is triggered by experiences such asexercise orfear-causing situations. This responsedilates pupils, increases heart rate, mobilizes energy, and diverts blood flow from non-essential organs toskeletal muscle. These effects together tend to increase physical performance momentarily.
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:
There were (at least) two different types of neurotransmitters released from sympathetic nerve terminals, or
There were (at least) two different types of detector mechanisms for a single neurotransmitter.
The first hypothesis was championed byWalter Bradford Cannon andArturo Rosenblueth,[1] 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, whenHenry 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 toergotoxine, the blood pressure decreased.[2][3] 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,[4] 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.[5] 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 oftwo 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,[6] 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.
The mechanism of adrenoreceptors. Adrenaline or noradrenaline arereceptor ligands to eitherα1,α2 or β-adrenoreceptors. Theα1 couples toGq, which results in increased intracellularCa2+ and subsequentsmooth muscle contraction. Theα2, on the other hand, couples toGi, which causes a decrease in neurotransmitter release, as well as a decrease ofcAMP activity resulting in smooth muscle contraction. The β receptor couples toGs and increases intracellularcAMP activity, resulting in e.g.heart muscle contraction, smooth muscle relaxation andglycogenolysis.
The mechanism of adrenoreceptors. Adrenaline or noradrenaline arereceptor ligands to eitherα1,α2 or β-adrenoreceptors. Theα1 couples toGq, which results in increased intracellularCa2+ and subsequentsmooth muscle contraction. Theα2, on the other hand, couples toGi, which causes a decrease in neurotransmitter release, as well as a decrease ofcAMP activity resulting in smooth muscle contraction. The β receptor couples toGs and increases intracellularcAMP activity, resulting in e.g.heart muscle contraction, smooth muscle relaxation andglycogenolysis.There are two main groups of adrenoreceptors, α and β, with 9 subtypes in total:
α receptors are subdivided intoα1 (aGq coupled receptor) andα2 (a Gi coupled receptor)[7]
β receptors are subdivided intoβ1,β2 andβ3. All 3 are coupled toGs proteins, but β2 and β3 also couple to Gi[7]
Gi and Gs are linked toadenylyl 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 includecAMP-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.[8]
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.
Subtype unspecific α agonists (see actions above) can be used to treatrhinitis (they decreasemucus secretion). Subtype unspecific α antagonists can be used to treatpheochromocytoma (they decreasevasoconstriction caused by norepinephrine).[7]
The α2 receptor couples to the Gi/o protein.[20] It is a presynaptic receptor, causingnegative 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.
increasecardiac output by increasing heart rate (positivechronotropic effect), conduction velocity (positivedromotropic effect), stroke volume (by enhancing contractility – positiveinotropic effect), and rate of relaxation of the myocardium, by increasing calcium ion sequestration rate (positivelusitropic effect), which aids in increasing heart rate
smooth muscle relaxation throughout many areas of the body, e.g. inbronchi (bronchodilation, seesalbutamol),[19]GI tract (decreased motility), veins (vasodilation of blood vessels), especially those to skeletal muscle (although this vasodilator effect of norepinephrine is relatively minor and overwhelmed by α adrenoceptor-mediated vasoconstriction)[24]
^abThere is no α1C receptor. There was a subtype known as C, but it was found to be identical to one of the previously discovered subtypes. To avoid confusion, naming was continued with the letter D. Before June 1995 α1A was named α1C. α1D was named α1A, α1D or α1A/D.[32]
^Cannon WB, Rosenbluth A (31 May 1933). "Studies On Conditions Of Activity In Endocrine Organs XXVI: Sympathin E and Sympathin I".American Journal of Physiology.104 (3):557–574.doi:10.1152/ajplegacy.1933.104.3.557.
^Marsh DT, Pelletier MH, Rose CA (Feb 1948). "The comparative pharmacology of the N-alkyl-arterenols".The Journal of Pharmacology and Experimental Therapeutics.92 (2):108–20.PMID18903395.
^abcdeRang HP, Ritter JM, Flower RJ, Henderson G (2016).Rang and Dale's pharmacology (8th ed.). United Kingdom: Elsevier. p. 179.ISBN9780702053627.OCLC903083639.
^Prischich, Davia; Gomila, Alexandre M. J.; Milla-Navarro, Santiago; Sangüesa, Gemma; Diez-Alarcia, Rebeca; Preda, Beatrice; Matera, Carlo; Batlle, Montserrat; Ramírez, Laura; Giralt, Ernest; Hernando, Jordi; Guasch, Eduard; Meana, J. Javier; de la Villa, Pedro; Gorostiza, Pau (2020). "Adrenergic modulation with photochromic ligands".Angewandte Chemie International Edition.60 (7):3625–3631.doi:10.1002/anie.202010553.hdl:2434/778579.ISSN1433-7851.PMID33103317.
^Elliott J (1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction".Journal of Veterinary Pharmacology and Therapeutics.20 (4):308–17.doi:10.1046/j.1365-2885.1997.00078.x.PMID9280371.
^Moro C, Tajouri L, Chess-Williams R (2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria".Urology.81 (1): 211.e1–7.doi:10.1016/j.urology.2012.09.011.PMID23200975.
^Kamalakkannan G, Petrilli CM, George I, et al. (2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure".The Journal of Heart and Lung Transplantation.27 (4):457–61.doi:10.1016/j.healun.2008.01.013.PMID18374884.
^Basic & Clinical Pharmacology. United States of America: MCGraw-Hill Education. 2018. p. 148.ISBN978-1-259-64115-2.
^Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (December 2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system".Pharmacological Reviews.52 (4):595–638.PMID11121511.
