Acetylcholine ACh

Acetylcholine mediates two different types of activity via corresponding receptors - muscarinic and nicotinic - which relate to the pharmacological activities of two natural prodncts, mnscarine and nicotine. The former type of action occurs in nerve synapses and the latter at nenromnscnlar jnnctions and peripheral ganglia. The term cholinergic is nsed for the general effects of acetylcholine. 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

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Acetylcholine Precursors. Early efforts to treat dementia using cholinomimetics focused on choline [62-49-7] (12) supplement therapy (Fig. 3). This therapy, analogous to L-dopa [59-92-7] therapy for Parkinson s disease, is based on the hypothesis that increasing the levels of choline in the brain bolsters acetylcholine (ACh) synthesis and thereby reverses deficits in cholinergic function. In addition, because choline is a precursor of phosphatidylcholine as well as ACh, its supplementation may be neuroprotective in conditions of choline deficit (104). 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Acetylcholine (Ach) is an ester of acetic acid and choline with the chemical formula CH3COOCH2CH2N+ (CH3)3. ACh functions as a chemical transmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in a wide range of organisms, humans included. Neurotransmitter involved in behavioral state control, postural tone, cognition and memory, and autonomous parasympathetic (and preganglionic sympathetic) nervous system. 

Primarily hydrolyses esters with short acyl moiety, such as acetylcholine (ACh). It is the major ChE in human blood, muscle and brain cells. AChE mRNA is 20-fold more abundant than BChE mRNA. 

The neurotransmitter acetylcholine (ACh) exerts its diverse pharmacological actions via binding to and subsequent activation of two general classes of cell surface receptors, the nicotinic and the mAChRs. These two classes of ACh receptors have distinct structural and functional properties. The nicotinic receptors,... 

The nicotinic receptor (nAChR) comprises a family of receptor subtypes that respond to the neurotransmitter acetylcholine (ACh) and the tobacco alkaloid nicotine. 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

The PNS has two neurohormones (neurotransmitters) acetylcholine (ACh) and acetylcholinesterase (ACliE). ACh is a neurotransmitter responsible for die transmission of nerve impulses to effector cells of die parasympathetic nervous system. ACh plays an important role in die transmission of nerve impulses at synapses and myoneural junctions. ACh is quickly... 

The AChR is composed of five subunits, ql2Pi - A neurotoxin attaches to the a subunit. Since there are 2 mol of the a subunits, 2 mol of neurotoxins attach to 1 mol of AChR. A neurotransmitter, acetylcholine (ACh), also attaches to the a subunit. When the ACh attaches to the AChR, the AChR changes conformation, opening up the transmembrane pore so that cations (Na" ", K ) can pass through. By this mechanism the depolarization wave from a nerve is now conveyed to a muscle. The difference between neurotoxin and ACh is that the former s attachment does not open the transmembrane pore. As a consequence, the nerve impulse from a nerve cannot be transmitted through the postsynaptic site (27). 

Traditionally receptors have been classified according to their pharmacology. Each neurotransmitter acts on its own family of receptors and these receptors show a high degree of specificity for their transmitter. Thus, the receptors on which acetylcholine (ACh) works do not respond to glutamate (or any other neurotransmitter) and vice versa. Diversity of neurotransmitter action is provided by the presence of multiple receptor subtypes for each neurotransmitter, all of which still remain specific to that neurotransmitter. This principle is illustrated by the simple observations outlined in... 

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...

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 ... 

FIGURE 7.14 Time-course of G-protein-mediated activation of GIRK potassium channels in rabbit sinoatrial node cells, (a). Outward current evoked by a 33-msec, 50-nA iontophoretic pulse of acetylcholine (between arrows), (b). Response of the unclamped cell to an iontophoretic pulse of acetylcholine (ACh). (Record (a) is adapted with permission from Trautwein et al., in Drug Receptors and Their Effectors, Birdsall, N. J. M., Ed., Macmillan, New York, 1980, pp. 5-22 record (b) is adapted with permission from Noma, in Electrophysiology of Single Cardiac Cells, Noble, D. and Powell, T., Eds., Academic Press, San Diego, CA, 1987, pp. 223-246.)... 

The two most common neurotransmitters released by neurons of the ANS are acetylcholine (Ach) and norepinephrine (NE). Several distinguishing features of these neurotransmitters are summarized in Table 9.3. Nerve fibers that release acetylcholine are referred to as cholinergic fibers and include all preganglionic fibers of the ANS — sympathetic and parasympathetic systems all postganglionic fibers of the parasympathetic system and sympathetic postganglionic... 

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)] (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)[ (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert) and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott Hobson, 2002 Jones, 2003). The following neurotransmitters function to promote W (1) acetylcholine (ACh LDT/PPT, BFB) (2) noradrenaline (NA LC) (3) serotonin (5-HT DRN, MRN) (4) histamine (HA TMN) (5) glutamate (GLU mPRF, BFB, thalamus) (6) orexin (OX LH) and (7) dopamine (DA VTA, SNc) (Zoltoski et al, 1999 Monti, 2004). 

Intracerebroventricular infusion of CST-14 dramatically increases the amount of slow wave activity in rats, at the expense of wakefulness. The mechanism by which CST-14 enhances cortical synchronization has been established through the interaction of CST-14 with acetylcholine, a neurotransmitter known to be involved in the maintenance of cortical desynchronization. Application of acetylcholine (ACh) in the anesthetized animal increases fast activity, and this effect is blocked with the simultaneous addition of CST-14. These data suggest that CST-14 increases slow wave sleep by antagonizing the effects of ACh on cortical excitability. In addition to this mechanism, cortistatin may enhance cortical... 

Acetylcholine (ACh) The first neurotransmitter to be discovered. It is located at numerous synapses and neuroeffector junctions, in both the central and peripheral nervous systems. 

Isotonic muscle contraction was used to measure the effects of selected nematode FaRPs on the body-wall muscle of H. contortus. AF2 was found to have inhibitory effects on muscle activity and inhibited acetylcholine (ACh) -induced contractions in the worm whereas AF8 had excitatory effects on the muscle and enhanced ACh-induced contractions (Marks et al., 1999a). There were obvious differences in the methodologies used to evaluate the effects of these peptides on Haemonchus muscle compared with those used to examine these peptide effects on Ascaris. How comparable the results are has yet to be determined. 

FIGURE 1.7 Simultaneous measurements of force (upper traces) and NO concentration (lower traces) in an endothelium intact (+E) segment of rat superior mesenteric artery contracted with 0.5 J,M noradrenaline (NA) and relaxed with either 10pM acetylcholine (ACh) (a), or 10 pM SNAP (b). Panel C shows a similar measurement in the rat superior mesenteric artery after mechanical endothelial cell removal. As can be seen in C, ACh addition does not cause NO production from the artery but shows an NO increase upon SNAP addition causing artery relaxation. W = washout. (Reprinted with permission from Blackwell Publishing [120].)... 

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