Acetylcholine cholinergic neuron

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

Acetylcholine is synthesised in nerve terminals from its precursor choline, which is not formed in the CNS but transported there in free form in the blood. It is found in many foods such as egg yolk, liver and vegetables although it is also produced in the liver and its brain concentration rises after meals. Choline is taken up into the cytoplasm by a high-affinity (Am = 1-5 pM), saturable, uptake which is Na+ and ATP dependent and while it does not appear to occur during the depolarisation produced by high concentrations of potassium it is increased by neuronal activity and is specific to cholinergic nerves. A separate low-affinity uptake, or diffusion (Am = 50 pM), which is linearly related to choline concentration and not saturable, is of less interest since it is not specific to cholinergic neurons. 

The development of antibodies against ChAT allowed the distribution of neurons producing acetylcholine in the nervous system to be revealed (Mesulam et al., 1983 Armstrong et al., 1983 Jones Beaudet, 1987 Vincent Reiner, 1987). In the context of control of wakefulness and REM sleep two groups of cholinergic neurons are of primary importance. Neurons located in the basal forebrain and medial septum provide the cholinergic innervation of the cerebral... 

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Berlanga M., Simpson T., Alcantra A. (2005). Dopamine D5 receptor localization on cholinergic neurons of the rat forebrain and diencephalon a potential neuroanatomical substrate involved in mediating dopaminergic influences on acetylcholine release. J. Comp. Neurol. 492, 34-49. 

The synaptic action of acetylcholine is unique among neurotransmitters in that it is terminated by hydrolysis rather than by transport (Ch. 11). Consequently, cholinergic neurons recover choline, rather than acetylcholine, via... 

Choline is supplied to the neuron either from plasma or by metabolism of choline-containing compounds 193 A slow release of acetylcholine from neurons at rest probably occurs at all cholinergic synapses 194 The relationship between acetylcholine content in a vesicle and the quanta of acetylcholine released can only be estimated 194 Depolarization of the nerve terminal by an action potential increases the number of quanta released per unit time 194 All the acetylcholine contained within the cholinergic neuron does not behave as if in a single compartment 194... 

All the acetylcholine contained within the cholinergic neuron does not behave as if in a single compartment. 

Adrenaline (epinephrine)-producing (adrenergic) and acetylcholine secreting (cholinergic) neurones of the autonomic nervous system have direct and complimentary effects on the tone of blood vessels. 

Pharmacology Donepezil enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase (AChE). Donepezil s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Pharmacokinetics ... 

Varicosity showing processes of synthesis and storage of acetylcholine within a cholinergic neuron. Also shown are the release of acetylcholine (exocytosis) and the location of acetylcholinesterase, which inactivates acetylcholine. 

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. 

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer s disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration. 

Preclinical studies have found reductions in brain acetylcholine content and disruption of the activity of cholinergic neurons following prenatal exposure to opiates (Robinson, 2000). Other work has documented increased hypothalamic norepinephrine content and tyrosine hydroxylase immunoreactivity following prenatal exposure to opiates (Vathy et ah, 2000). 

Whitehouse PJ, Price DL, Clark AW, et al Alzheimer disease evidence for selective loss of cholinergic neurons in the nucleus basahs. Ann Neurol 10 122-126, 1981 Whitehouse PJ, Price DL, Struble RG, et al Alzheimer s disease and senile dementia—loss of neurons in the basal forebrain. Science 215 1237-1239, 1982 Whitehouse PJ, Hedreen JC, White CL, et al Basal forebrain neurons in dementia of Parkinson s disease. Ann Neurol 13 243-248, 1983 Whitehouse P, Martino A, Antuono P, et al Nicotinic acetylcholine binding sites in Alzheimer s disease. Brain Res 371 146-151, 1986 Whitehouse PJ, Martino AM, Marcus KA, et al Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 45 722-724, 1988 Whitton PS, Sama GS, O Connell MT The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal diasylates in vivo. Neuropharmacology 39 1-4, 1991 Whitworth P, Kendall DA Lithium selectively inhibits muscarinic receptor-stimulated inositol tetrakisphosphate accumulation in mouse cerebral cortex slices. J Neurochem 51 258-265, 1988... 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

Administration of presynaptically active antagonists, i.e., substances that may trigger the synthesis and increased release of acetylcholine by presynaptic cholinergic neurons. It appears that this approach has not been tested systematically yet. 

A number of pathways contain acetylcholine, including neurons in the neostriatum, the medial septal nucleus, and the reticular formation. Cholinergic pathways appear to play an important role in cognitive functions, especially memory. Presenile dementia of the Alzheimer type is reportedly associated with a profound loss of cholinergic neurons. However, the specificity of this loss has been questioned because the levels of other putative transmitters, eg, somatostatin, are also decreased. 

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