Cholinergic neurons vesicles

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... 

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 transmitter is present throughout the cholinergic neurones and exists within the axon terminals in vesicles. About 1% of the vesicles are the readily releasable store that maintains transmitter release but more than 80% is in motor nerve endings in the releasable store, which is released in response to a nerve impulse. The remainder of ACh is in the so-called stationary store. The release of ACh may be spontaneous or in response to nerve impulses. Spontaneous release of ACh results in the production of random miniature endplate potentials. It is, however, in response to a nerve impulse that we see a large release of ACh provided there is adequate calcium present in the extracellular fluid. Evoked release of ACh usually results in the production of an endplate potential due to depolarisation of the motor endplate. 

The terminals of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the synaptic portion of the cell membrane (Figure 6-3) as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane. The large vesicles contain a high concentration of peptide cotransmitters (Table 6-1), while the smaller clear vesicles contain most of the acetylcholine. Vesicles are initially synthesized in the neuron soma and transported to the terminal. They may also be recycled several times within the terminal. 

Krapivinsky G, Mochida S, Krapivinsky L, Cibulsky SM, Clapham DE. 2006. The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release. Neuron 52 485-496. 

Acetylcholine Is the ester formed between acetylcoenzyme A and choline by the action of choline acetyltransferase In the presynaptic cholinergic neurons. Most of the choline used to blosynthesize acetylcholine comes via uptake from the synaptic space, where It Is produced from the hydrolysis of acetylcholine by acetylcholinesterase, a serine hydroxylase. Additionally, some choline Is blosynthesized In the presynaptic neurons from serine (Fig. 44.11). Once formed, acetylcholine Is stored In vesicles from which It Is released on stimulation. 

In 1926, Otto Loewi discovered that acetylcholine was the principal neurotransmitter of the parasympathetic nervous system. As with other neurotransmitters, acetylcholine is synthesized and stored in vesicles within presynaptic neurons. Ninety percent of the cholinergic neurons in the brain are muscarinic, controlling salivation,sweating, dyspnea, diarrhea, vertigo, confusion, weakness and coma. Acetylcholine binds to muscarinic receptors on smooth muscle cells, innervated by post-synaptic fibers of the parasympathetic nervous system. The thalamus and cerebellar cortex have nicotinic receptors, i diile most other regions of the brain have muscarinic neurons. 

Cholinergic neurons. Neurons in which choline acetyltransferase synthesizes acetylcholine, accumulates it in synaptic vesicles and releases it, upon depolarization, in the quantal mode. Those neurons located in the septal/ subcortical and cortical regions of the brain are responsible for cognitive and memory functions. Cholinergic motor neurons of anterior horns of medulla oblongata form neuro-muscular synapses responsible for voluntary movements of striated muscles. 

The synaptic vesicles are thought to represent one of the compartments containing a stable form of bound ACh. However, bound ACh is also found in the cytoplasm of nerve endings and in the axons and the cell-bodies of cholinergic neurons where no vesicles have been observed. 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Akert K, Sandri C. An electron-microscopic study of zinc iodide-osmium impregnation of neurons. I. Staining of synaptic vesicles at cholinergic junctions. Brain Res 1968 7 286-295. 

As ACh is synthesized, it is stored in the neuron or ganglion in at least three different locations. Eighty-five percent of all ACh is stored in a depot and can be released by neuronal stimulation it is always the newly synthesized neurotransmitter that is released preferentially. The surplus ACh can be released by K depolarization only. Finally, there is stationary ACh, which cannot be released at all. It has been assumed that the neurotransmitter in cholinergic and some other neurons is released through the exocytosis of small transmitter-filled synaptic vesicles. 

Fora basic account of synapses in general, see the text by Threadgold 877). Synapses have been examined in a number of genera, e.g. Diphyllobothrium, Echinococcus and Hymenolepis 277, 726,936,941,943). In the plerocercoid of Diphyllobothrium dendriticum, synapses are formed between neurites in which the presynaptic neurite contains (a) both dense-core vesicles and clear vesicles or b) small clear vesicles only (Fig. 2.10). The former correspond closely to the dense-core vesicles of aminergic neurones, and have been tentatively classified as aminergic synapses (277), whilst the latter are classified as cholinergic synapses. These neurones are discussed further below. 

Careful monitoring of the membrane potential of the muscle membrane at a synapse with a cholinergic motor neuron has demonstrated spontaneous, intermittent, and random 2-ms depolarizations of about 0.5-1.0 mV in the absence of stimulation of the motor neuron. Each of these depolarizations is caused by the spontaneous release of acetylcholine from a single synaptic vesicle. Indeed, demonstration of such spontaneous small depolarizations led to the notion of the quanta release of acetylcholine (later applied to other neurotransmitters) and thereby led to the hypothesis of vesicle exocytosis at synapses. The release of one acetyl-choline-containing synaptic vesicle results In the opening of about 3000 ion channels In the postsynaptic membrane, far short of the number needed to reach the threshold depolarization that induces an action potential. Clearly, stimulation of muscle contraction by a motor neuron requires the nearly simultaneous release of acetylcholine from numerous synaptic vesicles. 

They bind initially to ganglioside in the neuromuscular jimction, one subunit then being internalized as with the diphtheria toxin (Box 29-A). Botulinum toxins specifically enter motor neurons, while tetanus toxin is taken up via synaptic vesicle endocytosis by both peripheral and central neurons. Retrograde axonal transport carries the toxin into the central nervous system and across synaptic clefts into cholinergic intemeurons, which are poisoned. 

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