Acetylcholine cholinergics based

Taylor R F, Marenchic I G and Cook E J 1988 An acetylcholine receptor-based biosensor for the detection of cholinergic agents Anal. Chim. Acta 213 131-8 Taylor R F, Marenchic I G and Cook E J 1993 Receptor-based biosensors VS Patent 5 192 507... 

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). 

Acetylcholine receptors have been classified into subtypes based on early studies of pharmacologic selectivity 186 The intrinsic complexity and the multiplicity of cholinergic receptors became evident upon elucidation of their primary structures 189... 

Acetylcholine is the neurotransmitter that mediates both volitional and involuntary contractions of the bladder. Bladder smooth muscle cholinergic receptors are mainly of the M2 variety however, M3 receptors are responsible for both emptying contraction of normal micturition and involuntary bladder contractions, which can result in UI. Therefore, most pharmacologic antimuscarinic therapy is anti-M3 based. 

Acetylcholine (9.12) binds both types of cholinergic receptors muscarinic and nicotinic (Figure 9.9). The names of these receptor types were based on muscarine (9.13) and nicotine (9.14), selective agonists for each receptor. A muscarinic response is characterized by nausea, salivation, and tearing. Nicotinic responses are noted by an acceleration of the heart rate. Acetylcholine s ability to elicit a response from both subtypes of receptors may imply that different conformations of acetylcholine may be responsible for binding to each receptor. 

Acetylcholinesterase (AChE) catalyses the hydrolysis of the ester bond of acetylcholine to yield choline and acetate (Sussman et al., 1991). This is a critical reaction for the termination of impulses transmitted through cholinergic synapses. It is a highly efficient catalyst, with reaction rates approaching the diffusion limit. Its overall structure resembles the lipases with an active site gorge. Above the base of the gorge is the reactive serine to be activated by the classical (Ser-200...His-440...Glu-327) catalytic triad. 

Alzheimer s disease is characterized by a progressive impairment of cognitive functions including the loss of memory and the inability to perform basic daily life (56). Based on the cholinergic hypothesis, these symptoms are the results of the reduction in brain acetylcholine activity due to the catabolism of acetylcholine by ACHE (57). 

The main toxic effect of the OPs is the inhibition of the acetylcholine esterase (AChE) in the synapses and neuromuscular junctions, causing cholinergic crisis, which eventually leads to seizures, respiratory arrest and death. There are considerable differences in the dynamic of clinical manifestations and impairment induced by nerve agents and OP insecticides (slower onset, dependent on metabolic activation, prolonged effect based on their accumulation in certain tissues and subsequent systemic release). 

The muscarinic cholinergic system has quite a different mode of operation in that the receptor is connected to the final action by a chain of events. Thus its response is slower than the nicotinic, where the receptor and ion channel are closely connected. Five distinct muscarinic receptors have been identified in mammals, based on anatomical location, genetic analysis, function, and amino acid sequence. All of them have seven transmembrane domains [166, 167, 168, 169]. The N- terminal domain outside the cell binds acetylcholine or other ligands at a site that includes an aspartate residue, while the C-terminal domain inside the cell is coupled to a so-called G-protein , which is initially bound to guanosine diphosphate (GDP), but exchanges it for guanosine triphosphate (GTP) when activated by its transmitter. The activated G-protein then activates phospholipase C, which hydrolyzes phosphoinositides to release 1,4,5-inositol triphosphate [170]. The final action depends on which type of cell is involved so that in some types ion channels are opened just as with the nicotinic receptor, but in other cases other processes are affected, for example the release of dopamine [171]. Since there are these differences... 

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