Adrenoreceptors

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 29.10.2020

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Synonym(s)

Adrenergic receptors; Adreno receptors; alpha receptor; alpha receptors; beta receptor; beta receptors; ( e ) Adrenergic receptor

Definition
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Adrenoceptors are the group of transmembrane, G-protein-coupled receptors (GPCRs), which bind to the catecholamines noradrenaline and adrenaline and can trigger a signal cascade on the pre- or postsynaptic side (see overview of the different receptor types; see also Bencivenga L et al. 2019). Adrenoceptors are thus responsible for the effects mediated by adrenaline and noradrenaline.

Classification
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Depending on the structure, distribution and second messengers, a fundamental distinction is made between the main groups:

  • adrenergic alpha-receptors
  • and
  • adrenergic beta receptors.

These two main groups are further subdivided into subtypes due to their different effects:

  • α1 receptors
  • α2 receptors

and

  • β1 receptors
  • β2 receptors
  • β3 receptors.

alpha receptors:

Adrenoreceptors of the type alpha, in short alpha-receptors, are subdivided intoα1- andα2-receptors. There are 3 subtypes of both alpha-receptor types. The subtypes of both receptor types are only imprecisely characterized due to the lack of selective antagonists:

  • α1A-receptor subtype
  • α1B- Receptor subtype
  • α1D- Receptor subtype

The alpha1-arenoreceptors are mainly found in the presynaptic membrane of sympathetic and also parasympathetic neurons, but also on the cell membrane of adipocytes. They contribute to the regulation of sympathetic nervous system activity and influence a number of sympathetic reactions, e.g. to smooth muscles in vessels, bronchi, hair follicles (goose bumps), the urogenital tract and the gastrointestinal tract (see table). It is known that the α1A receptor subtype mediates vasoconstriction, the α1B receptor subtype causes the known positive inotropic effect on the heart of the α1 receptor:

Theα2 adrenoceptors can be further subdivided into:

  • α2A- receptor subtype
  • α2B- Receptor subtype
  • α2C- Receptor subtype

Vasoconstriction mediated by the presynapticα2 receptor is mediated by theα2B receptor. The activation of theα2C-receptor leads to the activation of aGi-protein(= inhibitory G-protein), which inhibits adenylate cyclase (AC) and thus leads to a decrease in cAMP levels.

beta receptors:

Beta-receptors are distinguished between:

  • β1- Receptor subtype
  • β2- Receptor subtype
  • β3- Receptor subtype

β1 adrenoceptors are found as sympathetic nervous system effectoreceptors in the heart, kidney and fatty tissue, but also in other tissues. They have a higher affinity for adrenaline compared to noradrenaline. Cardiac effects are also predominantly triggered via the β1 receptor subtype. This receptor type is predominantly expressed in the heart muscle cells. Only 25% of the receptors belong to the subtype β2. The activation of the beta1-adrenoreceptors leads to an increase of the cAMP level in the cells. Cyclic AMP activates the heart muscle and relaxes the smooth vascular muscles. In the heart muscle, the increase in cAMP leads to an activation of the cAMP-dependent protein kinase A (PKA). This posphorilizes the voltage-dependent L-type Ca++ channel of the heart muscle cell and thus ensures the positive inotropic effect. At the vascular muscles, PKA phosphorylation leads to relaxation of the smooth muscle cells via 2 different enzyme steps (deactivation of myosin light chain kinase, activation of Ca++-ATPase).

Furthermore, the lipolytic effect is mediated via theβ1 receptor subtype as well as the increased release of renin. The latter in turn leads to stimulation of the renin-angiotensin-aldosterone system and thus to an increase in peripheral blood pressure.

β2-adrenoceptors: Theβ2-adrenoceptors are the most common β-receptors found in the periphery; they are found in most organs influenced by the sympathetic nervous system as well as ubiquitously in the smooth muscle. The effect of the sympathetic nervous system is mediated byβ2 adrenoceptors in most target tissues; their activation leads to relaxation of smooth muscles, especially in the bronchi, blood vessels, uterus and intestine. In addition, the release of insulin is stimulated by the pancreatic beta cells, which has a partially anabolic effect (Johnson M (2006). Beta2-adrenoceptors are also expressed on immune cells.

β3 andβ4 adrenoceptors: These can also be detected in adipose and other tissues. Theβ3-adrenergic receptor(β3-AR) is an important regulator of various physiological functions, such as thermogenesis in brown adipose tissue, lipolysis in white adipose tissue, negative inotropic effect in cardiomyocytes and dilation of vascular muscles.β3 AR mutants associated with obesity, diabetes, cardiovascular disease and other disorders have been shown to be involved (Yang LK et al. 2019).

Remark: It is also conceivable that other receptors sensitive to catecholamines exist.

General therapy
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Pharmacological use: The adrenoceptors can be inhibited selectively or non-selectively, non-specifically by various drugs, so-called alpha and beta blockers. Stimulation of the adrenoceptors by receptor agonists is also possible. Adrenalin and noradrenalin itself are used as emergency therapeutic agents.

α-receptor antagonists(alpha-receptor blockers): Inhibitors of theα1-adrenoceptors(selective α1-receptor antagonists), are used in the treatment of hypertension (e.g. Doxazosin). Alpha-blockers with a selectivity for the receptorα1A subtype(e.g. tamsulosin), have also been shown to be effective in the therapy of benign prostatic hyperplasia. An alpha-blocker with selectivity forα2 adrenoceptor, yohimbine, has been shown to be important in the symptomatic treatment of erectile dysfunction.

α-receptor agonists(alpha-sympathomimetics) are drugs that act agonistically on α-adrenoceptors. Therapeutically, they are used as nasal sprays to reduce swelling of the nasal mucosa.

α2 receptor agonists are important as antihypertensives and in the symptomatic treatment of glaucoma. The α2-receptor agonists also include the imidazolines clonidine and moxonidine and the dopa analogue α-Methyldopa.

β-receptor antagonists(beta-receptor blockers ) are pharmaceuticals with a broad medical application spectrum. They are mainly used in the treatment of hypertension, coronary heart disease, chronic heart failure, cardiac arrhythmia and migraine.

β2-receptor agonists(β2-sympathomimetics ) are mainly used in pneumology for acute therapy of bronchial asthma. In obstetrics they are used as tocolytics.

Tables
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adrenoreceptors and the effect they mediate (table varies according to Graefe KH et al. 2016)

α1 receptors(signal transduction by Gq/11 = phospholipase-C coupled G protein):

Smooth muscle culture: vasoconstriction, dilator pupillae (contraction), hair follicle muscle (contraction), sphincter in the GI tract (contraction), bronchial muscle (contraction); urogenital tract (contraction e.g. of the bladder neck muscles and uterus)

heart muscle: positive inotropic effect

Salivary glands: secretion of serous saliva ↑

CNS: Action potential frequency in the sympathetic nervous system ↑

α2 receptors(signal transduction by Gi/o; protein Gi = inhibitory G protein)

Vessels: Vasoconstriction

Gastrointestinal tract:

  • Smooth Musculature: Relaxation
  • Glands: secretion ↓

Fatty tissue: Lipolyse↓

Pancreas: Insulinfreisetzung↓

Blood: Thrombozytenaggregation↑

Presynaptic regulation of transmitter release

  • Autoreceptor: Noradrenaline release ↓
  • heteroreceptor: Acetylcholinfreisetzung↓

Adrenal medulla: Adrenalinfreisetzung↓

CNS:

  • Action potential in Sympathikus↓
  • Action potential in the cardiac vagus ↑
  • Sedation
  • Analgesia beta1-receptors (signal transduction by GS = small protein with cAMP-dependent reaction)

β1 receptors(signal transduction by GS):

GI: smooth muscles (relaxation)

  • Myocardium:
  • positive inotropic
  • positive lusiotropic
  • positive chronotropic
  • positive dromotropic

glands:

  • Salivary glands: Sekretion↑
  • Bronchial glands: Sekretion↑

Kidney: Reninsekretion↑

Fatty tissue: Lipolyse↑

Corpus pineale: Melatoninsynthese↑

β2 receptors(signal transduction by GS; activated AC, cAMP↑)

Smooth musculature:

  • Vasodilation
  • Bronchodilation
  • Urogenital tract (relaxation)
  • Uterus (tocolysis)

Eye: Widening of Schlemm's canal

Bronchial glands: Sekretion↑

Blood:

  • Platelet aggregation: ↑
  • Mediator release from Mastezllen↓

Skeletal muscles:

  • Glykogenolyse↑
  • Activity of the Na+-K+-ATPase (hypokalemia)
  • Rest tremor

Presynaptic regulation of transmitter release (norepinephrine release ↑)

  • Insulin release ↑
  • Glukonfreisetzung↑

Fatty tissue: Lipolyse↑

Liver cell:

  • Glykogenolyse↑
  • Glukoneogenese↑
  • Glykogensynthese↑

β3 receptor (signal transduction by GS)

Fatty tissue: Lipolysis

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Last updated on: 29.10.2020