Neurotransmitters release processes

Stimulation of the neuron lea ding to electrical activation of the nerve terminal in a physiologically relevant manner should eUcit a calcium-dependent release of the neurotransmitter. Although release is dependent on extracellular calcium, intracellular calcium homeostasis may also modulate the process. Neurotransmitter release that is independent of extracellular calcium is usually artifactual, or in some cases may represent release from a non-neuronal sources such as gha (3). 

Numerous processes modulate neurotransmitter synthesis, presynaptic excitabihty, neurotransmitter release, post-synaptic receptors, and post-synaptic excitabihty. 

Psychoactive drugs can influence neurotransmission at its five different stages (Chapter 2). First, they may modify the biosynthesis of a neurotransmitter. Second, they can increase or decrease their storage within the presynaptic neuron. Third, they may stimulate or inhibit neurotransmitter release from the synaptic bouton. Fourth, they may affect the binding of the neurotransmitters to its receptor. Finally, they can retard the neurotransmitter s inactivation. Some examples of each of these stages will be given below, but it should be noted that many drugs affect several of these processes. 

Neurons constitute the most striking example of membrane polarization. A single neuron typically maintains thousands of discrete, functional microdomains, each with a distinctive protein complement, location and lifetime. Synaptic terminals are highly specialized for the vesicle cycling that underlies neurotransmitter release and neurotrophin uptake. The intracellular trafficking of a specialized type of transport vesicles in the presynaptic terminal, known as synaptic vesicles, underlies the ability of neurons to receive, process and transmit information. The axonal plasma membrane is specialized for transmission of the action potential, whereas the plasma... 

In the classic model of synaptic vesicle recycling in nerve terminals, synaptic vesicles fuse completely with the plasma membrane and the integrated vesicle proteins move away from the active zone to adjacent membrane regions (Fig. 9-9A). In these regions, clathrin-mediated synaptic vesicle endocytosis takes place rapidly after neurotransmitter release (within seconds) [64]. The process starts with the formation of a clathrin-coated pit that invaginates toward the interior of the cell and pinches off to form a clathrin-coated vesicle [83]. Coated vesicles are transient organelles that rapidly shed their coats in an ATP/chaperone dependent process. Once uncoated, the recycled vesicle fuses with a local EE for reconstitution as a synaptic vesicle. Subsequently, the recycled synaptic vesicle is filled with neurotransmitter and it returns to the release site ready for use. This may be the normal pathway when neurotransmitter release rates are modest. Clathrin/ EE-based pathways become essential when synaptic proteins have been incorporated into the presynaptic plasma membrane. 

Chemical transmission between nerve cells involves multiple steps 167 Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells 168 A variety of methods have been developed to study exocytosis 169 The neuromuscular junction is a well defined structure that mediates the presynaptic release and postsynaptic effects of acetylcholine 170 Quantal analysis defines the mechanism of release as exocytosis 172 Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis 174 Presynaptic events during synaptic transmission are rapid, dynamic and interconnected 175... 

Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells. The fundamental similarity between the events in the nerve terminal that control neurotransmitter... 

Neurotransmitter release induced by potassium-dependent depolarization is a physiologically relevant way to investigate pyrethroid effects on calcium-dependent neurotransmitter release since this process is independent of voltage-sensitive sodium channels [71]. Furthermore, potassium-stimulated calcium influx and subsequent neurotransmitter release by synaptosomes is blocked by a variety of voltage-sensitive calcium channel antagonists but not by TTX [4, 71, 72]. 

Chemical messengers, or neurotransmitters, are normally released when an action potential reaches the synaptic terminals. This process is entirely Ca2+-dependent. Intracellular Ca2+ causes movement of neurotransmitter-containing synaptic vesicles toward the membrane. Removal of Ca2+ will prevent this process, preventing neurotransmitter release even if an action potential arrives. 

In certain neurons, a different type of synapse, called a gap junction, may be formed. Gap junction transmission occurs through membrane channels made of six subunits, which directly connect with other postsynaptic gap junction channels. When the channels open, there is a continuity of cytoplasm and exchange of ions between the two neurons. This mode of transmission is faster because it does not involve the time-consuming processes of neurotransmitter release, diffusion across the synapse, and receptor binding. 

Over 100 years ago, a debate was raging between the two most famous neuroscientists in the world concerning the nature of the nervous system. Golgi believed that all neurons were connected in a nerve net or syncytium whereas Ramon y Cajal believed that neurons were separated from each other by tiny spaces called synapses. Cajal proved to be correct, and it was later learned that neurons communicate across the synapse by releasing chemical substances known as neurotransmitters or by releasing electrical charges. Because chemical neurotransmission is much more common than electrical transmission, especially in the brain, and it is chemical neurotransmission that is modulated by psychiatric medicines, our discussion will focus on the chemotransmitter process. In simplest terms, the process of chemical neurotransmission occurs in three steps neurotransmitter production, neurotransmitter release, and neurotransmitter action on specific receptors. 

The sequence of events that result in neurotransmission of information from one nerve cell to another across the s)mapses begins with a wave of depolarization which passes down the axon and results in the opening of the voltage-sensitive calcium charmels in the axonal terminal. These charmels are frequently concentrated in areas which correspond to the active sites of neurotransmitter release. A large (up to 100 M) but brief rise in the calcium concentration within the nerve terminal triggers the movement of the synaptic vesicles, which contain the neurotransmitter, towards the synaptic membrane. By means of specific membrane-bound proteins (such as synaptobrevin from the neuronal membrane and synaptotagrin from the vesicular membrane) the vesicles fuse with the neuronal membrane and release their contents into the synaptic gap by a process of exocytosis. Once released of their contents, the vesicle membrane is reformed and recycled within the neuronal terminal. This process is completed once the vesicles have accumulated more neurotransmitter by means of an energy-dependent transporter on the vesicle membrane (Table 2.3). 

In addition to the physiological process of autoinhibition, another mechanism of presynaptic inhibition has been identified in the peripheral nervous system, although its precise relevance to the brain is unclear. In the dorsal horn of the spinal cord, for example, the axon terminal of a local neuron makes axo-axonal contact with a primary afferent excitatory input, which leads to a reduction in the neurotransmitter released. This is due to the local neuron partly depolarizing the nerve terminal, so that when the axon potential arrives, the change induced is diminished, thereby leading to a smaller quantity of transmitter being released. In the brain, it is possible that GABA can cause presynaptic inhibition in this way. 

C. The purpose of this question is to clarify the cellular mechanism of analgesia produced by morphine. First, morphine blocks the transmission of nociceptive impulses. In that case, the relevant question is how nociceptive impulses are transmitted via the release of pronociceptive neurotransmitters. The question then is to determine which intracellular process favors a block of release of neurotransmitters. The correct answer is C because calcium is required for neurotransmitter release. Blocking potassium efflux and increasing calcium channel phosphorylation produce functional depolarization and neurotransmitter release. Opioids are coupled to Gj (inhibitory proteins) that decrease cAMP. 

There are three principal classes of opiate receptors, designated x, K, and 5, and there exist a number of drugs that are specific for each of these receptor types. However, most of the clinically used opiates are quite selective for the preceptor the endogenous opiates enkephalin, endorphin and dynorphin are selective for the p and 5, 5 and k receptors respectively. When activated by opioids these receptors produce biochemical signals that block neurotransmitter release from nerve terminals, a process that underlies their blockade of pain signaling pathways as well as other effects, such as constipation, diuresis, euphoria, and feeding. 

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