Synaptic junctions

The actual transmission of signals across a synaptic junction is a complicated chemical process that depends on a release of a neurotransmitter from the trans-... 

Populations of receptors that are excluded from synaptic junctions. These may be distributed over neuronal cell bodies or located around but not directly beneath synapses (perisynaptic). Some receptors have become specialised to setve an extrasynaptic function producing a tonic level of activity in response to ambient levels of neurotransmitter. This tonic current can be used to maintain homeostatic control over neuronal excitation. 

Functions of nNOS include long-term regulation of synaptic transmission in the CNS (long-term potentiation, long-term depression), whereas there is no evidence for an involvement of nNOS-derived NO in acute neurotransmission. Retrograde communication across synaptic junctions is presumed to be involved in memory... 

Afferent input from cutaneous and visceral nociceptors is known to converge on spinal neurons, which accounts for the referral of pain between visceral and cutaneous structures (e.g. cardiac pain gets referred to the chest and left upper arm in patients suffering from angina pectoris). Projection neurons in the spinal dorsal horn project to cell nuclei in supraspinal areas such as the thalamus, brainstem and midbrain. Of these, the synaptic junctions in the thalamus play a very important role in the integration and modulation of spinal nociceptive and non-nociceptive inputs. Nociceptive inputs are finally conducted to the cortex where the sensation of pain is perceived (Fig. 1). The mechanisms via which the cortex processes nociceptive inputs are only poorly understood. 

BZ is usually disseminated as an aerosol with the primary route of entry into the body through the respiratory system the secondary route is through the digestive tract. BZ blocks the action of acetylcholine in both the peripheral and central nervous systems. As such, it lessens the degree and extent of the transmission of impulses from one nerve fiber to another through their connecting synaptic junctions. It stimulates the action of noradrenaline (norepinephrine) in the brain, much as do amphetamines and cocaine. Thus, it may induce vivid hallucinations as it sedates the victim. Toxic delirium is very common. 

The first identified Ascaris FaRP, AF1 (KNEFIRFamide), and the structurally related peptide, AF2 (KHEYLRFamide), have been found to inhibit locomotory waves when injected into adult worms (Cowden et al., 1989 Cowden and Stretton, 1993). Their effects on body-wall muscle strips are biphasic, comprising a transient relaxation followed by an extended period of increased contractile activity (Maule et al., 1995b Bowman et al., 1996). When using muscle strips that have had the motor nerve cords removed, only the inhibitory actions of AF1 and AF2 are seen (Maule et al., 1995b). This suggests that the inhibitory phase is due to post-synaptic effects on body-wall muscle in the worm. In contrast, the excitatory effects are nerve-cord dependent and are not observed in muscle strips that have been denervated. Another possibility is that the peptides interact with receptors at the post-synaptic junction - these are also removed in specimens that have had the motor nerve cords removed. 

Fannon, A M. and Colman, D. R. A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron 17 423 34,1996. 

Uchida, N., Honjo, Y., Johnson, K. R., Wheelock, M. J. and Takeichi, M. The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. /. Cell Biol. 135 767-779,1996. 

A process similar to endocytosis occurs in the reverse direction when it is known as exocytosis (Figure 5.11). Membrane-bound vesicles in the cytosol fuse with the plasma membrane and release their contents to the outside of the cell. Both endocytosis and exocytosis are manifestations of the widespread phenomenon of vesicular transport, which not only ferries materials in and out of cells but also between organelles, e.g. from the endoplasmic reticulum to the Golgi and then to the lysosomes or to the plasma membrane for secretion (Chapter 1). Many hormones are also secreted in this way, as are neurotransmitters from one nerve into a synaptic junction that joins two nerves (Chapters 12 and 14). 

Information transfer between two nerves in the brain occurs at synaptic junctions, across which chemical messengers (neurotransmitters) diffuse. The neurotransmitter binds to a receptor on the postsynaptic neurone, changing its membrane potential. If the membrane potential decreases, this either initiates an action potential or increases the likelihood that a further depolarisation, from stimulation by another nerve, will initiate an action potential. Such a neurotransmitter is described as excitatory. In contrast, if it increases the membrane potential, it reduces the likelihood of initiation of an action potential, such a... 

Action potentials are the means whereby information is passed from one neuron to an adjacent neuron. The balance between the excitatory and inhibitory impulses determines how many action potentials will reach the axonal terminal and, by releasing a specific type of neurotransmitter from the terminal, influence the adjacent neuron. Thus, in summary, chemical information in the form of small neurotransmitter molecules released from axonal terminals is responsible for changing the membrane potential at the synaptic junctions which may occur on the dendrites or directly on the cell body. The action potential then passes down the axon to initiate the release... 

Acetylcholine (ACh) as a transmitter. ACh serves as mediator at terminals of all postganglionic parasympathetic fibers, in addition to fulfilling its transmitter role at ganglionic synapses within both the sympathetic and parasympathetic divisions and the motor end-plates on striated muscle. However, different types of receptors are present at these synaptic junctions ... 

Figure 1. Schematic diagram of a synaptic junction demonstrating the principle of chemical neurotransmission.

FIGURE 23.2 Sites of action of tricyclic antidepressants at the synaptic junction. (Modified from Baldes-sarini (1996). 

Release Liberation of the neurotransmitter from vesicle electrical firing of a nerve leads to fusion of vesicles with the cell wall, allowing the neurotransmitter to be released into the synaptic junction... 

Figure 30-10 (A) Schematic drawing of a synapse. (B) Electron micrograph showing the synaptic junctions in the basal part (pedicle) of a retinal cone cell of a monkey.403 Each pedicle contains synaptic contacts with 12 triads, each made up of processes from a bipolar cell center that carries the principal output signal and processes from two horizontal cells that also synapse with other cones. A ribbon structure within the pedicle is characteristic of these synapses. Note the numerous synaptic vesicles in the pedicle, some arranged around the ribbon, the synaptic clefts, and the characteristic thickening of the membranes surrounding the cleft (below the ribbons). Micrograph courtesy of John Dowling.

Cocaine inhibits the presynaptic reuptake of the neurotransmitters norepinehrine, serotonin, and dopamine at synaptic junctions. This results in increased concentrations in the synaptic cleft. Since norepinephrine acts within the sympathetic nervous system, increased sympathetic stimulation is produced. Physiological effects of this stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia.3 CNS stimulation results in increased alertness, diminished appetite, and increased energy. The euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition of serotonin and dopamine reuptake. Cocaine also acts as a local anesthetic due to its ability to block sodium channels in neuronal cells.3... 

Schematic diagram of a synaptic junction in which acetylcholine is the chemical transmitter. Arrival of an action potential at the terminus of the presynaptic cell (top) stimulates Ca2+ uptake, which triggers release of acetylcholine (ACh) from vesicles near the terminus of the...

In both rods and cones, the light-sensitive molecules reside in a layered system of membranes at one end of the cell (figs. S2.2 and S2.3). The membranes form by invaginations of the plasma membrane near the middle of the cell. In cone cells, the membranes remain contiguous with the plasma membrane. In rods, they pinch off to form a stack of autonomous flattened vesicles, or disks, in the outer segment of the cell. This region of the cell is connected by a thin cilium to the inner segment, which is packed with mitochondria and ribosomes. The basal part of the cell ends in a synaptic junction with another neural cell called a bipolar cell. 

From the viewpoint of the chemist, the brain presents an almost limitless frontier. The brain, as a center for communication control, has been shown by anatomists and physiologists to be composed of a network of neurons that make contact with one another mostly by release of chemicals at synaptic junctions (neurotransmission). There are astronomical numbers of these synaptic junctions,and there 1s also a complex array of chemical transmitters and chemical modulators Involved 1n neurotransmission. Many of these transmitters and modulators have not yet been identified. The physiological actions of these substances are diverse (they both excite and depress activity) so we must also postulate that many different molecular structures are Involved 1n receptor functions even for the very same transmitter or modulator. 

Sertraline (Zoloft, 7.9) is an antidepressant that blocks the reuptake of serotonin (7.10), a neurotransmitter, from the synaptic junction (Figure 7.19). Despite the effectiveness and market success of sertraline, the drug has an unfavorably large Vd of 30 L/kg. Sertraline extensively distributes into tissues and out of the bloodstream. If a drug leaves the blood, it cannot be cleared by... 

Venlafaxine (Effexor, 11.57) blocks the reuptake of serotonin and norepinephrine from the synaptic junction and acts as an antidepressant (Scheme 11.5). The primary metabolic pathway of venlafaxine is (9-demethylation (11.58), which is mediated by CYP2D6. CYP2D6 has variable activity across different populations. Groups with a more active form of CYP2D6 tend to show more side effects from venlafaxine. 

HT, A.50), norepinephrine (NE, A.51), and dopamine (DA, A.52), in the synaptic junction (Figure A.15). Drugs that treat depression have been classified into several structural/ functional categories. 

Tricyclic antidepressants (TCAs) are the oldest antidepressants. TCAs consist of a seven-membered ring both fused with two benzenes and bearing a tethered amine. Examples include imipramine (A.53) and amitriptyline (A.54) (Figure A.16). TCAs primarily act by blocking the reuptake of NE from the synaptic junction and prolonging the time of action of NE. TCAs, however, also affect the action of 5-HT and DA and therefore have more side effects than most antidepressants. 

Fig. 2 Electron micrograph of synapses. The image shows synapses formed by cultured cortical neurons from mouse. Note abundant synaptic vesicles in nerve terminals adjacent to synaptic junctions that are composed of presynaptic active zones and postsynaptic densities (open arrows point to postsynaptic densities of synaptic junctions synapse on the right contains two junctions). In addition to synaptic vesicles, two of the nerve terminals contain LDCVs (closed arrows). Calibration bar = 500 nm. (Image courtesy of Dr. Xinran Liu, UT Southwestern).

The investigation of DAT immunolabeling at the ultrastructural level (Nirenberg et al., 1997b) visualized the DAT in varicose and intervaricose segments of axons in both the NAc core and the shell, with an organization similar to that detected in the dorsal striatum. Symmetric synapses were seen in both the two main NAc subregions, but DAT-immunoreactive processes only rarely formed synaptic junctions. DAT was not detected over synaptic densities and was instead mostly distributed on the extrasynaptic portions of the plasma membranes, near appositions with somata, dendrites, dendritic spines and astrocytes. 

Q4 (B)These drugs act by blocking serotonin reuptake at synapses, thus increasing the level of serotonin at the synaptic junction. In increase in the level of serotonin may diminish the repetitive behaviours. 

Tetanus is characterised by a prolonged contraction of skeletal muscle fibres the neurotoxin responsible is from Clostridium tetani. The toxin initially binds to peripheral nerve terminals and is then transported within the axon and across synaptic junctions until it reaches the central nervous system (CNS). Here it attaches to ganghosides at the presynaptic inhibitory motor nerve endings and is taken up into the axon by endocytosis. The effect of the toxin is to block the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid), which are required to check the nervous impulse, leading to the generalised muscular spasms characteristic of tetanus. 

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