Receptors choline

Sobreviela, T., Clary, D. O., Reichardt, L. F., Brandabur, M. M., Kordower, J. H., and Mufson, E. J., TrkA-immunoreactive profiles in the central nervous system colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltrans-ferase, and serotonin, J. Comp. Neurol., 350, 587, 1994. 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

Acetyl choline is the natural neurotransmitter for the cholinergic receptor. Two distinct receptor subtypes have been characterized based on their binding affinity for either nicotine (189) and (190) or muscarine (191). 

Choline functions in fat metaboHsm and transmethylation reactions. Acetylcholine functions as a neurotransmitter in certain portions of the nervous system. Acetylcholine is released by a stimulated nerve cell into the synapse and binds to the receptor site on the next nerve cell, causing propagation of the nerve impulse. 

Thermodynamically it would be expected that a ligand may not have identical affinity for both receptor conformations. This was an assumption in early formulations of conformational selection. For example, differential affinity for protein conformations was proposed for oxygen binding to hemoglobin [17] and for choline derivatives and nicotinic receptors [18]. Furthermore, assume that these conformations exist in an equilibrium defined by an allosteric constant L (defined as [Ra]/[R-i]) and that a ligand [A] has affinity for both conformations defined by equilibrium association constants Ka and aKa, respectively, for the inactive and active states ... 

Del Castillo, J., and Katz, B. (1957). Interaction at end-plate receptors between different choline derivatives. Proc. Roy. Soc. Lond. B. 146 369-381. 

The open channel has in most cases a selective permeability, allowing a restricted class of ions to flow,for example Na+, K+, Ca++ or Cl- and, accordingly, these channels are called Na+-channels, K+-channels, Ca -channels and Cr-channels. In contrast, cation-permeable channels with little selectivity reject all anions but discriminate little among small cations. Little is known about the structures and functions of these non-selective cation channels [1], and so far only one of them, the nicotinic acetylcholine receptor (nAChR, see Nicotinic Receptors), has been characterized in depth [2, 3]. The nAChR is a ligand-gated channel (see below) that does not select well among cations the channel is even permeable to choline, glycine ethylester and tris buffer cations. A number of other plasma... 

Covalent regulation. Following occupation and activation of the M2 acetyl choline receptors, phospholipase C (PLC), is activated and both inositol (l,4,5)-trisphosphate (IP3), and diacylglycerol (DAG), are formed by hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2). 

As distinct from the acetyl choline receptor of the neuromuscular junction, the acetyl receptors of the viscera are not blocked by nicotine but are blocked by muscarine. Moreover, based on differences in the binding of the muscarinic antagonist, pirenzapine, the muscarinic acetyl choline receptors (mAChRs), are separated into two classes, viz. high affinity mj receptors, and low affinity m2 receptors. The latter predominates in the heart, cerebellum, and smooth muscle broadly. These different receptors mediate quite different actions. 

Nicotine is a component of Nicotiana tabacum, the tobacco plant. It is toxic to many insects because of its action upon the nicotinic receptor of acetyl choline. It has served as a model for a new range of insecticides, the neonicotinoids, which also act upon the nicotinic receptor (Salgado 1999). 

Murexine and related compounds have marked actions on the nicotine receptor as expected from choline esters (87-89). Toxins from the digestive glands of nudi-branchs have marked effects on the cardiovascular system of the rat (23). Antiviral and antibacterial substances have been obtained from molluscs (90,91). 

Del Castillo, J and Katz, B (1957) Interaction at endplate receptors between different choline... 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Low concentrations of solubilised jS-albumin inhibit ACh release in slices from rat hippocampus and cortex areas which show degeneration in AzD, but not in slices from the striatum which is unaffected. While not totally specific to ACh, since some inhibition of NA and DA and potentiation of glutamate release have been reported, this effect is achieved at concentrations of A/i below those generally neurotoxic. Since jS-amyloid can inhibit choline uptake it is also possible (see Auld, Kar and Quiron 1998) that in order to obtain sufficient choline for ACh synthesis and the continued function of cholinergic neurons, a breakdown of membrane phosphatidyl choline is required leading to cell death (so-called autocannibalism), /i-amyloid can also reduce the secondary effects of Mi receptor activation such as GTPase activity... 

Figure 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

The acetyl choline receptor is a ligand-gated ion channel that allows cations to flow out of the neuron to initiate an action potential during neurotransmission (Fig. 9-6). When the receptor binds acetylcholine, a conformational change of the receptor opens a membrane channel that conducts ions. 

The binding of acetyl choline to the ACETYL CHOLINE RECEPTOR opens a gate that allows cations to pass through the membrane. This is called a ligandgated channel. 

The postsynaptic membrane opposite release sites is also highly specialized, consisting of folds of plasma membrane containing a high density of nicotinic ACh receptors (nAChRs). Basal lamina matrix proteins are important for the formation and maintenance of the NMJ and are concentrated in the cleft. Acetylcholinesterase (AChE), an enzyme that hydrolyzes ACh to acetate and choline to inactivate the neurotransmitter, is associated with the basal lamina (see Ch. 11). 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

Cerlie, T. H., Van-Rossum-Fikkert, S. E., Van Dijk, W. J., Brej, K., Smit, A. B. and Sixma, T. Nicotine and carbamyl-choline binding to nicotinic receptors as studied in AChBP crystal structures. Neuron 41, 907-914, 2004. 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

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