Synapse neurotransmitter release

Figure 1.6 Presynaptic inhibition of the form seen in the dorsal horn of the spinal cord, (a) The axon terminal (i) of a local neuron is shown making an axo-axonal contact with a primary afferent excitatory input (ii). (b) A schematic enlargement of the synapse, (c) Depolarisation of the afferent terminal (ii) at its normal resting potential by an arriving action potential leads to the optimal release of neurotransmitter, (d) When the afferent terminal (ii) is already partially depolarised by the neurotransmitter released onto it by (i) the arriving acting potential releases less transmitter and so the input is less effective...

At least two classes of regulated secretion can be defined [54]. The standard regulated secretion pathway is common to all secretory cells (i.e. adrenal chromaffin cells, pancreatic beta cells, etc.) and works on a time scale of minutes or even longer in terms of both secretory response to a stimulus and reuptake of membranes after secretion. The second, much faster, neuron-specific form of regulated secretion is release of neurotransmitters at the synapse. Release of neurotransmitters may occur within fractions of a second after a stimulus and reuptake is on the order of seconds. Indeed, synaptic vesicles may be recycled and ready for another round of neurotransmitter release within 1-2 minutes [64]. These two classes of regulated secretion will be discussed separately after a consideration of secretory vesicle biogenesis. 

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... 

Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis. In most cases in the CNS and PNS, chemical transmission does not occur unless Ca2+ is present in the extracellular fluid. Katz and Miledi [16] elegantly demonstrated the critical role of Ca2+ in neurotransmitter release. The frog NMJ was perfused with salt solution containing Mg2+ but deficient in Ca2+. A twin-barrel micropipet, with each barrel filled with 1.0mmol/l of either CaCl2 or NaCl, was placed immediately adjacent to the terminal. The sodium barrel was used to depolarize the nerve terminal electrically and the calcium barrel to apply Ca2+ ionotophoretically. Depolarization without Ca2+ failed to elicit an EPP (Fig. 10-6A). If Ca2+ was applied just before the depolarization, EPPs were evoked (Fig. 10-6B). In contrast, EPPs could not be elicited if the Ca2+ pulse immediately followed the depolarization (Fig. 10-6C). EPPs occurred when a Ca2+ pulse as short as 1 ms preceded the start of the depolarizing pulse by as little as 50-100 (xs. The experiments demonstrated that Ca2+ must be present when a nerve terminal is depolarized in order for neurotransmitter to be released. 

Tyrosine phosphorylation plays an important role in synaptic transmission and plasticity. Evidence for this role is that modulators of PTKs and PTPs have been shown to be intimately involved in these synaptic functions. Among the various modulators of PTKs, neuro-trophins have been extensively studied in this regard and will be our focus in the following discussion (for details of growth factors, see Ch. 27). BDNF and NT-3 have been shown to potentiate both the spontaneous miniature synaptic response and evoked synaptic transmission in Xenopus nerve-muscle cocultures. Neurotrophins have also been reported to augment excitatory synaptic transmission in central synapses. These effects of neurotrophins in the neuromuscular and central synapses are dependent on tyrosine kinase activities since they are inhibited by a tyrosine kinase inhibitor, K-252a. Many effects of neurotrophins on synaptic functions have been attributed to the enhancement of neurotransmitter release BDNF-induced increase in neurotransmitter release is a result of induced elevation in presynaptic cytosolic calcium. Accordingly, a presynaptic calcium-depen-dent phenomenon - paired pulse facilitation - is impaired in mice deficient in BDNF. 

A unified model for mechanotransduction allows comparison of mechanoreceptors from many organisms and cell types. Mechanoreceptors nearly universally use ion channels for transducing sensory information. Mechanoreceptors are either neurons or are neuroepithelial cells with synapses, and the currency of the nervous system is the membrane potential. Opening an ion channel allows a cell quickly and extensively to modulate its membrane potential, and hence neurotransmitter release, the final step in mechanoreception at the cellular level. 

A second type of NMDA-receptor-independent LTP exists in the mossy-fiber pathway at the dentate granule cell-to-CA3 pyramidal cell synapse [19]. This form of LTP, termed mossy fiber-CA3 LTP, is believed to involve PKA activation in the presynaptic cell which leads to increased neurotransmitter release. However, the exact induction mechanism is not yet clear. 

The communication between neurons occurs at either gap junctions (electrical synapses) or chemical synapses with release of neurotransmitters from a presynaptic neuron and their detection by a postsynaptic nerve cell (Fig. 17.1). Neurotransmitters not used in the synaptic cleft are removed promptly by either uptake into adjacent cells, reuptake in the presynaptic neuron, or are degraded by enzymatic systems. 

Figure 17.1. Neurotransmission (specific case of peptidergic cells). Production of the peptides in the cel I body (1). Packing of the peptides i nto large dense core vesicles for further transport to the axons (2). Release of neuropeptides from the cell soma (3) dendrites (4) and outside of the synapse (5). Release of classic neurotransmitters in the synaptic cleft (6). G-protein-coupled type receptors, which act as peptide receptors. (See color insert.)...

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. 

The neurotransmitter at the sensory nerve-motor nerve synapse proved to be glutamate (incidentally, also the major excitatory neurotransmitter in the human brain). Eurther research established a basic molecular event associated with shortterm learning habituation caused the sensory neuron to release less glutamate into the synapse sensitization caused the sensory neuron to release more glutamate into the synapse. Thus, the amount of neurotransmitter released into the synapse correlates with the strength of the motor response. The release of glutamate induces an action... 

The sensory neuron from the tail makes a synapse with the modulating neuron, known as an intemeuron. Its job is to fine-tune the response of the sensory neuron to stimulation. Note that the intemeuron synapses with both the cell body and the presynaptic terminal of the sensory neuron. The neurotransmitter released by the intemeuron into these synapses is serotonin (also a key neurotransmitter in the human nervous system). The net effect of the serotonin release is to strengthen the connection between the sensory neuron and the motor neuron. It remains to explain how this happens that, too, has been tracked down in molecular detail. 

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. 

Figure 14.11 Effects of excitatory and inhibitory neurotransmitters on initiation of an action potential in response to a second neurotransmitter. If the neurotransmitter released from the presynaptic membrane is inhibitory, it will reduce the likelihood that the second neurotransmitter will initiate an action potential. If the neurotransmitter is excitatory, it will increase the likelihood that the second neurotransmitter will initiate an action potential in the postsynaptic neurone. The second neurotransmitter arises from synapses of other axons.

There is evidence that a number of closely related phosphoproteins associated with the synaptic vesicles, called synapsins, are involved in the short-term regulation of neurotransmitter release. These proteins also appear to be involved in the regulation of synapse formation, which allows the nerve network to adapt to long-term passage of nerve impulses. 

The neuroeffector roles of OA may be broadly classified as those in which it acts as a neurotransmitter, as a neuromodulator, and as a neurohormone (12). The distinction between these actions is not absolute, but a neurotransmitter, released into a synapse, tends to have a rapid, highly localized action on a neighboring cell, while a neurohormone tends to have a slower, more prolonged action on a large number of cellular elements, often at a considerable distance from the point of its release. A neuromodulator is a neurohormone, released locally or at a distance from its site of action, that regulates the excitability of another nerve, muscle or gland cell. 

Neurotransmitters in the strict sense are substances that are produced by neurons, stored in the synapses, and released into the synaptic cleft in response to a stimulus. At the post-synaptic membrane, they bind to special receptors and affect their activity. 

In addition to serotonin, reserpine also releases other neurotransmitters, especially dopamine and noradrenaline, from their stores in presynaptic nerve raidings. Furthermore, the action on the synapse of the neurotransmitters released in this way is limited because they undergo intracellular enzymatic degradation. 

Rimonabant CBi receptor agonist Decreases neurotransmitter release at GABAergic and glutamatergic synapses Approved in USA and Europe to treat obesity Smoking cessation is an off-label indication Major depression, including increased risk of suicide... 

N-type Ca2+ channels for instance are located at presynaptic termini of neurons where they are directly involved in the regulation of neurotransmitter release. Staining of the dorsal laminae of the rat spinal cord revealed a complementary distribution of class A and class B Ca2+ channels in nerve terminals in the deeper versus the superficial laminae. Many of the nerve terminals immunoreactive for class B N-type Ca2+ channels also contain substance P, an important neuropeptide in pain pathways, suggesting the N-type Ca2+ channels are predominant at synapses that carry nociceptive information to the spinal cord (Westernbroek etal., 1998). 

FIGURE 11-25 Fusion during neurotransmitter release at a synapse. 

L-type calcium channels are the primary trigger for excitation-contraction (EC) coupling in cardiac, skeletal, and smooth muscles (Bean, 1989). They are also found in most central and peripheral neurons where they in part control calcium-dependent gene expression, as well as in endocrine cells and many types of non-excitable cells where they contribute to a variety of processes including exocytotic release. Unlike most synapses in the brain and spinal cord that rely on P/Q- and N-type calcium channels for neurotransmitter release, (Wheeler et al., 1994), the presynaptic terminals in photoreceptor cells rely on the Cav1.4 (a1F) L-type calcium channel for mediating glutamate release (Tachibana et al., 1993 Nachman-Clewner et al., 1999). Photoreceptor neurotransmission is atypical first,... 

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