Nicotinic receptors acetylcholine binding with

Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N, Kerwin R, Perry R, Perry E (1999) Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia alpha-bungarotoxin and nicotine binding in the thalamus. J Neurochem 73 1590-1597 Couturier S, Bertrand D, Matter JM, Hernandez MC, Bertrand S, MiUar N, Valera S, Barkas T, Ballivet M (1990) A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is devel-opmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX. Neuron 5 847-856... 

The mechanisms of all the neurotransmitters function have not been well understood. One neurotransmitter, acetylcholine, has been studied intensely and will be discussed briefly here. The structure of acetylcholine is shown in Fig. 17.2, along with those of nicotine, serotonin and muscarine. Acetylcholine is released from the synapse and migrates to the next neuron surface nearby, and binds to a receptor. There are two types of acetylcholine receptor one is nicotinic , implying that it also binds nicotine, and the other muscarinic . Nicotine and muscarine (as seen in Fig. 17.2) have a common feature, i.e., a positively charged nitrogen such as acetylcholine. The receptor itself is an ion channel. When acetylcholine binds with the receptor, the ion channel opens up, and the inflow of Na and outflow of K ensues. The sudden change of the cationic concentration inside and outside of the postsynaptic neuron creates an... 

With endplate nicotinic receptors it has been found that, as well as activating the receptor, acetylcholine (ACh) blocks the ion channel. A possible mechanism to describe this situation (assuming for simplicity only a single agonist binding is required to activate the receptor) might therefore be ... 

Cytisine is a tricyclic quinolizidine alkaloid that binds with high affinity and specificity to nicotinic acetylcholine receptors. In principle, this compound can exist in several conformations, but semi-empirical calculations at the AM 1 and PM3 levels have shown that stmctures 19 and 20 are more stable than other possible conformers by more than 50 kcalmol-1. Both structures differ by 3.7 kcalmol 1 at the AMI level and 2.0 kcalmol 1 at the PM3 level, although this difference is much smaller when ab initio calculations are employed <2001PJC1483>. This conclusion is in agreement with infrared (IR) studies and with H NMR data obtained in CDCI3 solution, which are compatible with an exo-endo equilibrium < 1987JP21159>, although in the solid state cytisine has an exo NH proton (stmcture 19) (see Section 12.01.3.4.2). 

Stauffer, D.A., and Karlin, A. (1994) Electrostatic potential of the acetylcholine binding sites in the nicotinic receptor probed by reaction of binding-site cysteines with charged methanethiosulfonates. Biochemistry 33, 6840-6849. 

Nakanishi studied philanthotoxin (polyamine-amide) interaction with nicotinic acetylcholine ion-channel [58]. Philanthotoxin-133 (PhTX-133) is a noncompetitive channel-blocker found in venom of the wasp Philanthus. Nicotinic acetylcholine ion-channel is composed of five transmembrane subunits (a, o, P, y, and S), which forms a 270-kDa glycoprotein. The major acetylcholine binding sites are in the a,ex subunits. A 43-kDa cytoplasmic protein is associated non-covalently with the receptor, but interaction with the receptor is not essential for the channel opening (Fig. 6). 

Grenningloh G, Rienitz A, Schmitt B, Methfessel C, Zensen M, et al. 1987. The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 328 215. 

Grutter T, Ehret-Sabatier L, Kotzyba-Hibert E, Goeldner M. 2000. Photoaffinity labelling of Torpedo nicotinic receptor with the agonist [ H] DCTA identification of amino acid residues which contribute to the binding of the ester moiety of acetylcholine. Biochemistry 39 3034-3043. 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

Atropine, an alkaloid from Atropa belladonna, is the classical parasympatholytic compound. It competes with acetylcholine for the binding at the muscarinic receptor. Its affinity towards nicotinic receptors is very low, so that it does not interfere with the ganglionic transmission or the neuromotor transmission, at least in therapeutic dosages. However, in the central nervous system muscarinic receptor do play an important role and while atropine can penetrate the blood-brain barrier it exerts pronounced central effects. Atropine, like all other antagonists of the muscarinic acetylcholine receptor inhibit the stimulatory influence of the parasympathetic branch of the autonomous nervous system. All excretory glands (tear, sweat, salivary, gasto-intestinal, bronchi) are... 

Depending on which face it puts forward, a single dmg molecule may interact with more than one receptor and thus may have more than one pharmacophoric pattern. For example, one bioactive face of acetylcholine permits interaction with a muscarinic receptor, while another bioactive face of acetylcholine permits interaction with a nicotinic receptor (section 4.2). Similarly, the excitatory neurotransmitter glutamate may bind to a range of different receptors, such as the NMDA and AMPA receptors (section 4.7), depending upon the pharmacophoric pattern displayed by the glutamate molecule toward the receptor with which it is interacting. 

The nicotinic acetylcholine receptor has five subunits single copies of subunits /3, y, and 8, and two identical a subunits each with an acetylcholine-binding site. All five subunits are related in sequence and tertiary structure, each having four transmembrane helical... 

Conductance measurements showed that the nicotinic receptors contain channels permeable to Na+ and other cations and that they are acetylcholine-gated ion channels. Construction of a three-dimensional image from electron micrographs at various angles of tilt shows a tube with approximate pentagonal symmetry and a narrow channel through the center (Fig. 30-23).622 624 636 Acetylcholine binds to sites on the two a subunits 3 nm away from the ion channel. 

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