Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors , also muscarinic , muscarinic or muscarinic receptors , are membrane-based receptors that occur in the parasympathetic nervous system and bind the neurotransmitter acetylcholine (ACh) as a substrate ( acetylcholine receptors ), but can also be activated by muscarin . These receptors belong to the group of G protein-coupled receptors .
Reaction path
The reaction pathway when the muscarinic ACh receptors ( M 1 , M 3 , M 5 ) are activated is quite complex and takes place via the phosphoinositol system. In the first step, the membrane-based phospholipase C (PLC) is activated via a G protein (G q ) . The point of attack of this enzyme is the phosphatidylinositol-4,5-bisphosphate (PIP 2 ), a component of the cell membrane. In the brain, the fatty acid composition of this lipid is unusually uniform.
The PLC splits off the inositol trisphosphate (IP 3 ) from this phospholipid , which diffuses into the cytoplasm. The remaining diacylglycerol (DAG) remains in the membrane. In the cytoplasm, IP 3 then releases Ca 2+ from intracellular stores in the endoplasmic reticulum , which sets a whole series of biochemical processes in motion. Protein kinase C can attach to the membrane-bound DAG . With the help of Ca 2+ , the catalytic domain of the enzyme is then exposed. A phosphorylation of cellular proteins using the adenosine triphosphate then other mechanisms come into the cell in transition. Both systems (IP 3 and DAG) can work independently of one another and also reinforce one another.
The reaction pathway of the M 2 and M 4 receptors is different from the others. A receptor-controlled potassium channel is activated via the βγ subunit of an (inhibitory) G i protein and, at the same time, adenylate cyclase is inhibited via the α subunit. The increased potassium conductivity (I KACh current) causes the cell to hyperpolarize . (See excitation formation in cells, action potential )
construction
The molecular structure of the muscarinic ACh receptor (mAChR) is completely different from that of the nicotinergic . It consists of a continuous chain of around 400–500 amino acids. This spans the cell membrane with 7 transmembrane domains (TMs), each of which has an α-helix structure ( heptahelical receptor ). The amino-terminal end (N-terminus) is outside the cell (extracellular), the carboxy-terminal end (C-terminus) is intracellular. On the cytoplasmic side, the receptor is coupled to a GTP -binding protein ( G-protein ), which is responsible for further signal transduction . It is therefore classified in the family of G protein-coupled receptors . As with the nicotinergic ACh receptor, the body expresses different isoforms (subtypes) of the receptor in different tissues, they are numbered M 1 -M 5 , and have the following distribution:
- M 1 is the neural type in the brain , e.g. B. in the corpus striatum
- M 2 on the heart, on postganglionic neurons of the parasympathetic nervous system , which lower contractility and heart rate.
- M 3 is the mAChR of the smooth muscles of the vessels and the glands (e.g. salivary glands , pancreas ). M 3 is also present in the parietal cells of the stomach for hydrochloric acid production.
- M 4 and M 5 have not yet been finally characterized; we know about their occurrence in the brain. Research from Japan suggests that M 5 is responsible for vasodilation in cerebral arterioles and the release of dopamine in the striatum.
The receptors have also been found to a small extent in other tissues . The receptors differ in their pharmacokinetics , i. This means that they can be addressed to different degrees by different active ingredients (see below).
Function and medical significance
The abundance of this receptor gives it a wealth of functions.
M 1 receptor
In the brain , acetylcholine has an influence on cognitive abilities such as learning and attention via the M 1 receptor . Together with the nicotinergic acetylcholine receptor, the M 1 is held responsible for the delirious hallucinogenic effects of some drugs. The betel nut (fruit of Areca catechu ) is chewed by many people, especially in India . The contained agonistic acting parasympathomimetic Arecolin passes through the blood-brain barrier into the brain and exerts there the euphoric and stimulating effects. Also - albeit with an opposite, antagonistic ( parasympatholytic ) effect - thorn apple ( Datura stramonium ), deadly nightshade ( Atropa belladonna ) and henbane ( Hyoscyamus niger ) are used because of hyoscyamine and scopolamine . Acetylcholine has an influence on Parkinson's disease via the basal ganglia . Here it is responsible for the disorders of the extrapyramidal motor system (rest tremor , muscle rigidity ), but only because there is a dopamine deficiency , which leads to a relative acetylcholine excess . The drugs benzatropine and biperiden are given to the sick to block M 1 receptors in the striatum and thus reduce the suffering.
M 2 receptor
The M 2 receptor subtype is located in the heart , which is controlled by the parasympathetic nervous system and which has a negative dromotropic , negative chronotropic and indirectly negative inotropic effect on the heart . This is achieved via two mechanisms in the pacemaker cells of the heart in the sinus or AV node :
1. Inhibition of adenylyl cyclase via a Gα i protein and thus lowering of cAMP . This has an inhibiting influence on the HCN channel ("funny channel", I f ). This is responsible for the pacemaker current , a Na + inward current at the beginning of the depolarization phase : the inhibition delays the depolarization of the cells.
2. Acetylcholine activates the βγ subunit of the heterotrimeric Gi protein via the M 2 receptor, which activates the receptor-controlled potassium channel GIRK (G protein activated inwardly rectifying K + channel; also Kir3.x). This increases the potassium conductivity (current: I KACh ). Increased potassium conductivity leads to hyperpolarization of the cell. The cause is the larger number of K + ions that are now flowing out of the cell. This makes the rest potential more negative and more stable, i.e. it moves away from the threshold potential longer . Accordingly, the cell is more difficult to depolarize.
Pharmacologically, muscarine in particular has a stimulating effect on the M 2 receptor and atropine or especially (S) -hyoscyamine has an inhibitory effect .
The parasympathetic system is able to inhibit the sympathetic system directly. The reason for this are M 2 receptors, which are expressed on the surface of the sympathetic neurons and have an inhibitory effect through stimulation via acetylcholine from parasympathetic fibers. An example of this is the parasympathetic vasodilation of blood vessels by inhibiting the vasoconstriction mediated by the sympathetic nervous system.
M 3 receptor
Circulation : M 3 receptors are expressedby the endothelium . When activated, NO is synthesized, which has a relaxingeffecton the smooth muscle cells surrounding the vessels.
In the genitals , ACh causes the production of nitrogen monoxide (NO) via the M 3 receptor . NO acts as a vasodilator, i.e. This means that there is increased blood flow and thus an erection of the penis and the labia majora .
Acetylcholine has a bronchospastic effect on the bronchi , i. That is, the bronchial muscles (M 3 receptor) contract and narrow the airways. This is of great importance in COPD . Ipratropium is an antagonist of the mAChR and has a bronchodilator effect through inhalation, i.e. it expands the airways and can therefore be used for COPD therapy and as a reserve agent in the treatment of bronchial asthma .
In the parietal cells of the stomach, ACh acts on M 3 receptors in hydrochloric acid secretion.
The Sjogren's syndrome is an autoimmune disease in which the immune system attacks the body glands. One of the consequences is a dry mouth . These patients can be helped with pilocarpine . This drug particularly stimulates the M 3 receptors. For this reason it is also used to diagnose cystic fibrosis . Due to the inadequate reabsorption of Na due to the disease and the simultaneous stimulation of the sweat glands to produce sweat, sweat is very high in sodium.
Muscarinic ACh receptor on the eye
The accommodation of the eye and the width of the pupil are also adjusted via the muscarinic ACh receptor. The ophthalmologist uses atropine derivatives such. B. Homatropin (atropine itself works for up to twelve days and is therefore only suitable for therapeutic mydriasis ) in order to enlarge the pupils and to be able to see the fundus better ( ophthalmoscopy ). The use of hyoscyamine under the name Belladonna has the same background . In the past, women have dripped the juice of deadly nightshade into their eyes in order to get large pupils and thus correspond to an ideal of beauty.
Carbachol and pilocarpine , both of which stimulate the mAChR, are used in angle- closure glaucoma therapy, since the narrowing of the pupil improves the outflow of aqueous humor through Schlemm's canal .
See also
Individual evidence
- ^ Hans Christian Renckhoff: The influence of sphingolipids and analogues on GIRK currents of atrial cardiomyocytes . 2006.
- ^ R. Buhl et al .: German Respiratory League, German Society for Pneumology and Ventilation Medicine e. V. (Ed.): Guideline for diagnosis and therapy of patients with asthma (PDF) 2006.