Choline cholinergic transmission

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.

Sarter M, Parikh V. 2005. Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci 61 48-56. 

Despite the drawbacks of the cholinergic hypothesis, this idea has guided most of the researchers involved with AD and enormous resources have been invested in developing compounds that would directly (nicotinic and M, selective muscarinic agonists) or indirectly (acetylcholinesterase inhibitors, M2 selective muscarinic antagonists, acetylcholine releasers, high affinity choline uptake inhibitors) increase the level of cholinergic transmission in the brain. 

The neuropharmacology of the ionenes is presumably not restricted to interactions with AcChR. Choline re-uptake, release of transmitter, and esterase activity may also be affected by this class of polymers, since in all cases recognition sites for quaternary nitrogen functions are involved. Thus the present paper is no more than a beginning in the application of ionenes to the pharmacological and biochemical study of the various macromolecular structures functioning in cholinergic transmission. 

Furthermore, it has been demonstrated that ginsenoside Rbi increases the uptake of choline in central cholinergic nerve endings (Benishin, 1992), and facilitates the release of acetylcholine from hippocampal slices (Benishin et al, 1991 Lee et ah, 2001). These results clearly suggest that ginsenosides may facilitate learning and improve the basic synaptic transmission as well as nerve growth. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

At the neuromuscular junction, nicotinic function is enhanced by inhibition of AChE. However, unlike muscle nAChRs, some neuronal nAChRs, particularly those bearing the a7 subunit, recognize both acetylcholine and its metabolite choline as full agonists (Pereira et al., 2002). Therefore, cholinesterase inhibition may not necessarily enhance functions mediated by these nAChRs. In fact, cholinesterase inhibitors do not affect a7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick cUiary ganglia (Zhang et al., 1996). 

Evidence that acetylcholine is a chemical mediator of synaptic transmission elsewhere in the central nervous system is circumstantial but convincing. Acetylcholine is the transmitter substance from motor nerves, preganglionic autonomic fibres and the postganglionic fibres of the parasympathetic system to their respective effector cells. In all these fibres, the activity of choline acetyltransferase (choline acetylase), the enzyme responsible for the synthesis of acetylcholine, is high. Conversely, its activity is negligibly low in sensory nerve fibres and transmission from these fibres is demonstrably non-cholinergic in nature . It is reasonable, therefore, to... 

Barbiturates selectively depress transmission in autonomic ganglia and reduce nicotinic excitation by choline esters, an effect that may account for the fall in blood pressure produced by intravenous oxybarbiturates and by severe barbiturate intoxication. At skeletal neuromuscular junctions, the blocking effects of both tubocurarine and decamethonium are enhanced during barbiturate anesthesia. These actions probably result from the capacity of barbiturates at hypnotic or anesthetic concentrations to inhibit the passage of current through nicotinic cholinergic receptors. Several distinct mechanisms appear to be involved and little stereoselectivity is evident. 

The enzyme acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylcholine to acetate and choline to terminate nerve impulse transmission at cholinergic synapses. This enzyme binds nerve agents such as VX and sarin. Inhibition of AChE by these compounds and the closely related organophosphate pesticides results in constant... 

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