Cholinoceptors

Christopoulos A, Lanzafame A, Michelson E. Allosteric interactions at muscarinic cholinoceptors. Clin Exp Pharmacol Physiol 1998 25 185-194. 

Pappano, A.J., Cholinoceptor-blocking drugs, in Basic and Clinical Pharmacology, 8th ed., Katzung, B.G., Ed., Lange Medical Books/McGraw-Hill, New York, 2001, chap. 8. 

Schroder H, Zilles K, Luiten PG, Strosberg AD. 1990. Immu-nocytochemical visualization of muscarinic cholinoceptors in the human cerebral cortex. Brain Res 514 249-258. 

The ganglionic N-cholinoceptors apparently consist only of a and p subunits (a2P2). Some of the receptors for the transmitter y-aminobutyric acid (GABA) belong to this receptor family ... 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

Target tissues of 2"" parasympathetic neurons ACh Muscarine Atropine Muscarinic (M) cholinoceptor G-protein-coupled-receptor protein with 7 transmembrane domains... 

Sympathetic parasympathetic ganglia ACh Nicotine Trimethaphan Ganglionic type (o3p4) Nicotinic (N) cholinoceptor ligandgated cation channel formed by five transmembrane subunits muscular type (al2PlY5)... 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma... 

Substances acting antagonistically at the M-cholinoceptor are designated parasympatholytics (prototype the alkaloid atropine actions shown in red in the panels). Therapeutic use of these agents is complicated by their low organ selectivity. Possibilities for a targeted action include ... 

Gastric secretion. Stimulation of gastric acid production by vagal impulses involves an M-cholinoceptor subtype (M -receptor), probably associated with enterochromaffin cells. Pirenzepine (p. 106) displays a preferential affinity for this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only Ma-receptors. Mi-receptors have also been demonstrated in the brain however, these cannot be reached by pirenzepine because its lipophilicity is too low to permit penetration of the blood-brain barrier. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers (p. 166). 

The ganglionic effects of ACh can be blocked by tetraethylammonium, hexa-methonium, and other substances (ganglionic blockers). None of these has intrinsic activity, that is, they fail to stimulate ganglia even at low concentration some of them (e.g hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamyla-mine, trimethaphan) are typical receptor antagonists. 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

The cholinoceptor antagonist pi-renzepine, unlike atropine, prefers cho-linoceptors of the Mi type, does not penetrate into the OIS, and thus produces fewer atropine-like side effects (p. 104). The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by blocking Ml receptors on ECL cells or submucosal neurons. 

Muscle relaxants cause a flaccid paralysis of skeletal musculature by binding to motor endplate cholinoceptors, thus blocking neuromuscular transmission (p. 

Pancuronium is a synthetic compound now frequently used and not likely to cause histamine release or ganglionic blockade. It is approx. 5-fold more potent than d-tubocurarine, with a somewhat longer duration of actioa Increased heart rate and blood pressure are attributed to blockade of cardiac M2-cholinoceptors, an effect not shared by newer pancuronium congeners such as vecuronium and pipecuronium. 

Anticholinergics. Antagonists at muscarinic cholinoceptors, such as betuatropine and biperiden (p. 106), suppress striatal cholinergic overactivity and thereby relieve rigidity and tremor however, akinesia is not reversed or is even exacerbated. Atropinelike peripheral side effects and impairment of cognitive function limit the tolerable dosage. 

The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances. These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropine-like effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. 

Hi-receptor but also at muscarinic cholinoceptors, serotonin receptors, and adrenoceptors. This explains the atropine-like side effects of those drugs. The cationic amphophilic structure of these substances resemble that of antiarrhythmic agents which might explain the arrhythmogenic properties seen with some of these Hi-antagonists. 

After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). 

AccessMedicine Print Chapter 7. Cholinoceptor-Activating Cholinesterase-Inhibiting Drugs... 

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