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Neuromuscular Physiology
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
To stop the depolarization and muscle fiber contraction, a first step is the degradation of ACh. The enzyme AChE is located in the basement membrane near the sarcolemma and is positioned between the site of ACh release and the AChRs (109, 125, 127). Although AChE is continuously activated, ACh cannot alter the ACh–AChR interface because during depolarization there are more molecules of transmitter released than there are molecules of enzyme present in the basement membrane. After the opening of AChR channels, ACh molecules detach and diffuse toward the basement membrane. The transmitter is then deactivated by hydrolysis and transmission is eventually finished within a few milliseconds. ACh hydrolysis products, choline and acetic acid, are taken up by the axon terminals, converted into ACh, and repackaged into vesicles. Acetylcholine is re-synthesized from choline and acetyl coenzyme A catalyzed by choline acetyltransferase. The rate-limiting step in the synthesis of ACh is transport of choline into the nerve terminal via a high-affinity choline transporter (30).
Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
The acetyl CoA should be plentiful since it is provided from pyruvate formed by the metabolism of glucose. But it is not clear how acetyl CoA gets from the inner membrane of the mitochondria where it is formed to the cytoplasm of the neuron where ChAT is found. The rate-limiting step in the overall synthesis of ACh is believed to be the transport of choline into the neuron. Cholinergic neurons are believed to have a high affinity uptake transporter that can move choline into the cell by an active process. The Km for this high affinity choline uptake is 1 to 5 μM. Thus, with an estimated tissue concentration of about 10 μM, the transporter is expected to be saturated56 and increasing plasma or tissue concentration of choline would not be expected to increase ACh synthesis. However, several studies have shown that increased plasma levels of choline can increase ACh concentration in brain.1 The mechanism by which this occurs may be the transport of choline into the cell by a low affinity choline transporter that has also been identified (Km = 40 to 100 μM).57 There is also evidence that the Vmax of the high affinity choline transporter in nerves can increase when the neuron is stimulated, allowing it to take up more choline and synthesize more ACh under conditions of increased utilization.56 The importance of choline uptake as the rate-limiting factor in ACh synthesis is further emphasized by the fact that inhibition of this step results in a marked inhibition of ACh synthesis (e.g., hemicholinium).56,57
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
Choline is transported into the nerve by a transporter or “carrier” protein in the membrane. The choline transporter, referred to as ChT,19 has a high affinity for choline, which means that it avidly picks up choline from the surrounding area. It has, however, a limited number of transport sites, meaning that it can get filled up or saturated. Increasing the concentration of choline up to the point at which the sites become filled results in a proportional increase in the rate of choline transport. However, once all the transporters are occupied, the rate of transport becomes constant.
Immunothrombosis and thromboinflammation in host defense and disease
Published in Platelets, 2021
Kimberly Martinod, Carsten Deppermann
A substantial advance in the understanding of platelet–neutrophil interaction-mediated NET formation is the recent report of neutrophil SLC44A2 (Solute Carrier Family 44 Member 2) binding activated αIIbβ3 under flow [50], which provides mechanistic insight into the role of platelets in NET formation during thrombosis under conditions of shear stress. SLC44A2 encodes for choline transporter-like protein 2 (CTL-2), and was identified as a susceptibility locus for VTE risk [51]. In addition to the role in NET formation by neutrophils, SLC44A2 is also itself expressed by platelets and promotes their activation in response to thrombin via choline transport into mitochondria [52]. SLC44A2 therefore can contribute to thrombosis either directly within platelets, or via platelet-mediated NET formation.
Mechanistic comparison of current pharmacological treatments and novel phytochemicals to target amyloid peptides in Alzheimer’s and neurodegenerative diseases
Published in Nutritional Neuroscience, 2018
Neelima Ayyalasomayajula, Challa Suresh
Cholinergic system (Acetylcholine) plays an important role in learning and memory functions.43–46 Acetylcholine is synthesized from acetyl CoA and Choline by the enzyme Acetylcholine transferase. Then it was uptaken by synaptic vesicles by the enzyme vesicular Acetylcholine transferase. The vesicular Acetylcholine undergoes exocytosis upon reaching the synaptic cleft during depolarization and then binds to Nicotinic and Muscarinic receptors. Acetylcholine will then hydrolyzed promptly by the enzyme Acetylcholinesterase and releases acetate and choline, which is recycled to the presynaptic nerve terminal by choline transporter. Even picomolar or nanomolar concentrations of amyloid β in the cerebrospinal fluid play neuro-modulatory role in the regulation of cholinergic functions, which leads to memory loss and learning impairment.47 Reports suggested that when observed with the short-term exposure of amyloid peptide-induced cultures of rat cortical and hippocampal neurons, there was a decrease in the levels of Acetylcholine release, decreased uptake of choline into synaptic vesicles, and increase in excitability, whereas the long-term exposure of amyloid peptides in neuronal cultures leads to disruption of muscarinic receptor signaling and decrease in the activity of enzymes Choline acetyl transferase and Acetylcholine esterase.48–50
Pathophysiological effect of bladder outlet obstruction on the urothelium
Published in Ultrastructural Pathology, 2018
Grzegorz Niemczyk, Katarzyna Czarzasta, Piotr Radziszewski, Paweł Włodarski, Agnieszka Cudnoch-Jędrzejewska
The urothelium is a part of non-neuronal cholinergic system (NNCS) and its impact on bladder function is taken into account because its receptors are located in urothelial cells, interstitial cells, bladder afferents and detrusor cells.19 It is not clear which is the main enzyme responsible for acetylcholine (ACh) synthesis in urothelium – choline acetyltransferase (ChAT) or carnitine acetyltransferase (CarAT).19,20 It seems counterintuitive but ChAT expression is reduced in patient with BOO as opposed to controls, thus entails diminished release of ACh after its stimulation.20 The release of ACh probably occurs predominantly by organic cation transporter 1 and 3 (OCT1, 3), which may be less expressed in patients with BOO.19,20 In contrast choline transporter-1 (CHT1) was not affected which suggest unchanged reuptake mechanism.19