Adrenoceptors

Crystal structure of the β ₂ -adrenoceptor in complex with its ligand carazolol

Adrenergic receptors or adrenoceptors for short are receptors that are activated by the natural messenger substances adrenaline and noradrenaline . They are therefore responsible for the effects mediated by adrenaline and noradrenaline. Adrenoceptors play an important role , particularly in sympathetically innervated tissue. In addition, they come e.g. B. but also in the central nervous system and on platelets .

Classification

Adrenoceptors are class A G-protein-coupled receptors and as such are closely related to rhodopsin . The nine identified human receptor proteins are divided into three families based on their pharmacological and molecular biological properties:

• α ₁ -adrenoceptors with the subtypes α _1A , α _1B and α _1D , which can be found predominantly in blood vessels .
• α ₂ adrenoceptors with the subtypes α _2A , α _2B and α _2C , which can be found, for example, on blood platelets and on neurons of the autonomic nervous system and the central nervous system.
• β-adrenoceptors with the subtypes β ₁ , β ₂ and β ₃ , which are responsible in particular for the regulation of cardiac activity ( inotropy , chronotropy and dromotropy ) and the relaxation of smooth muscles (e.g. in bronchi ). β ₂ -adrenoceptors are also expressed on immune cells and play a role in CNS-immune communication.

In addition, based on different pharmacological properties, an "α _1L " -adrenoceptor was postulated as a phenotype of the α _1A -adrenoceptor and a "β ₄ " -adrenoceptor as a low-affinity variant of the β ₁ -adrenoceptor. A rodent receptor called the α _2D adrenoceptor turned out to be the orthologue of the human α _2A adrenoceptor.

The pharmacologist Raymond P. Ahlquist first classified the adrenoreceptors in 1948 .

structure

As for all G-protein-coupled receptors, a structure consisting of seven cell membrane spanning helices is assumed for the adrenoceptors . This could be confirmed on the basis of X-ray crystal structure data at least for the β ₁ and the β ₂ adrenoceptor. Just like rhodopsin, the adrenoceptors have an intracellular helix 8 (Hx8). In contrast to all other G protein-coupled receptors with a known crystal structure, an additional helix structure in the second extracellular loop (ECL2) near the ligand binding pocket was detected for both β ₁ and β ₂ adrenoceptors .

pharmacology

Drugs that interact with adrenoceptors are used in a variety of ways in drug therapy. Both agonists and antagonists are used. Epinephrine and norepinephrine themselves are used as emergency therapeutic agents.

Inhibitors of the α ₁ -adrenoceptors, which belong to the so-called alpha blockers , are used in particular in the treatment of high blood pressure . Alpha blockers with a selectivity for the α _1A subtype, for example tamsulosin , have also proven themselves in the treatment of benign prostatic hyperplasia . An alpha blocker with a selectivity for α ₂ -adrenoceptors, yohimbine , was important in the symptomatic treatment of erectile dysfunction . α- Sympathomimetics , substances that act agonistically on α-adrenoceptors, are used, among other things, as nasal sprays to decongest the nasal mucosa . α ₂ -adrenoceptor agonists are also important as antihypertensive drugs (blood pressure lowerers ) and in the symptomatic treatment of glaucoma .

Beta blockers have a very wide range of applications . They are used in particular in the treatment of high blood pressure, coronary artery disease , chronic heart failure , cardiac arrhythmias and migraines . In 1988 Sir James Whyte Black was honored with the Nobel Prize in Physiology or Medicine for their discovery . β ₂ sympathomimetics are used in pulmonary medicine for acute therapy in bronchial asthma and COPD and in obstetrics as tocolytics .

literature

• PP Griffin, M Schubert-Zsilavecz, H Strong: Inhibitors of beta-adrenoceptors . In: Pharmacy in our time . 33, No. 6, 2004, pp. 442-449. doi : 10.1002 / pauz.200400091 .
• S Guimarães, D Moura: Vascular adrenoceptors: an update . In: Pharmacol. Rev. . 53, No. 2, June 2001, pp. 319-356. PMID 11356987 .

Web links

• David Goodsell: Molecule of the Month: Adrenergic Receptors

Individual evidence

1. ↑ IJ Elenkov, RL Wilder et al .: The sympathetic nerve - an integrative interface between two supersystems: the brain and the immune system . In: Pharmacol Rev . 52, No. 4, 2000, pp. 595-638. PMID 11121511 .
2. ↑ JR Docherty: Subtypes of functional alpha1-adrenoceptor . In: Cell. Mol. Life Sci. . October 2009. doi : 10.1007 / s00018-009-0174-4 . PMID 19862476 .
3. ↑ JR Arch: Do low-affinity states of beta-adrenoceptors have roles in physiology and medicine? . In: Br. J. Pharmacol. . 143, No. 5, November 2004, pp. 517-518. doi : 10.1038 / sj.bjp.0705991 . PMID 15514247 . PMC 1575436 (free full text).
4. ↑ SG Rasmussen, HJ Choi, DM Rosenbaum et al .: Crystal structure of the human beta2 adrenergic G-protein-coupled receptor . In: Nature . 450, No. 7168, November 2007, pp. 383-387. doi : 10.1038 / nature06325 . PMID 17952055 .
5. ↑ V Cherezov, DM Rosenbaum, MA Hanson et al .: High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor . In: Science . 318, No. 5854, November 2007, pp. 1258-1265. doi : 10.1126 / science.1150577 . PMID 17962520 . PMC 2583103 (free full text).
6. ^ T Warne, MJ Serrano-Vega, JG Baker et al .: Structure of a beta1-adrenergic G-protein-coupled receptor . In: Nature . 454, No. 7203, July 2008, pp. 486-491. doi : 10.1038 / nature07101 . PMID 18594507 .