Synaptic area

As was mentioned before, neurotransmitters are synthesized within the neuron either in the cell body or in the synaptic area and stored in presynaptic vesicles. 

The taste receptor mechanism has been more fully described by Kurihara (1987). The process from chemical stimulation to transmitter release is schematically presented in Figure 7-4. The receptor membranes contain voltage-dependent calcium channels. Taste compounds contact the taste cells and depolarize the receptor membrane this depolarization spreads to the synaptic area, activating the voltage-dependent calcium channels. Influx of calcium triggers the release of the transmitter norepinephrine. 

Norepinephrine released into the synaptic area is rendered inactive either by O-methylation (primarily meta but some para) via catechol O-methyltransferase (13) or by uptake by the neuronal amine uptake system. Utilizing the inwardly-directed Na+ concentration gradient maintained by the neuronal membrane (Na+ + K+)-ATPase, norepinephrine is co-transported with Na+ in a facilitated diffusion process which appears to be carrier-mediated (14, lip). +... 

EAAC is, at least in the cerebral cortex, present throughout the dendritic ramifications, including the spines and is therefore close to the synapses (Conti et al., 1998). The pre-embedding technique used in the latter study enabled the authors to conclude that the spines contain EAAC, but not which parts of the spine membrane that contains EAAC (for review of the methods see Danbolt et al., 1998a). Thus, it is not known if EAAC is present only in the non-synaptic parts of the spine membrane or if it is also present in the synaptic area. Further, it is difficult to assess the importance of EAAC before information on the concentration becomes available. 

Fig. 8. Effects of disruption of endophilin and amphiphysin interactions on clathrin-mediated endocytosis at the reticulospinal synapse. (A) Electron micrograph of the lateral side of the active zone in a control synapse stimulated at 5 Hz. Note the presence of clathrin-coated pits with different shapes. (B) Electron micrograph of the comparable area of a synapse in an axon that was stimulated at 5 Hz for 30 min after injection of endophilin antibodies. Note the pocket-like membrane expansions (arrows) at the margin of the synaptic area and the appearance of numerous shallow coated pits (arrows). (C) A synapse in an axon which was stimulated at 0.2 Hz for 30 min after injection of a fusion protein containing the SH3 domain of amphiphysin linked to GST. Note the accumulation of constricted coated pits around the active zone. Scale bar, 0.2 pm. B, modified from Ringstad et al. (1999), Neuron 24, 143-154, with permission copyright is held by Cell Press. C, modified from Shupliakov et al. (1997a) Science 276 259-263, with permission copyright 1997 AAAS.

A second, nonchemical, NE-terminating process is simply diffusion away from the synaptic area. The quantitative significance of this is difficult to gauge since diffusion also brings the NE molecules into the clutches of the extraneural metabolism enzymes catechol-O-methyltransferase (COMT) and MAO. Here the catecholamines are taken up, Uptake 2(U2), into extraneural tissue and degraded. Unlike the neuronal reuptake process (Ui), this does not represent amine preservation. 

It is interesting that a hypotensive relapse occurs once the IV administration is discontinued. One explanation may be that the stored metaraminol being released from the NE-depleted neurons, since it is less effective as a pressor amine than NE, now acts as a false transmitter, actually having a hypotensive effect. Because of its a-CH3 it is not significantly affected by MAO (while the NE in the synaptic area is). Metaraminol will reaccumulate, be restored, and be re-released, thus prolonging the hypotensive effect. 

Thus there appear to be significant mechanistic differences the hydrazines inhibit MAO, the tertiary amine tricyclics seem to inhibit the serotonin amine pump, whereas the secondary amine ones seem better in switching off the NE reuptake mechanism. Table 12-18, however, shows that there is some overlap. Nevertheless, there is a thread of commonality—the net increase of amine neurotransmitters in the synaptic area—yet all these drugs require several weeks of treatment before objective results are noted. The biogenic amine hypothesis does not satisfactorily explain this. It is even more difficult to explain the antidepressant action of some of the second-generation drugs, such as mianserin (Fig. 12-26), that seem to have no significant effect on amine reuptake mechanism of either... 

Criteria for transmitter status To be accepted as a neurotransmitter. a candidate chemical must be present in higher concentration in the synaptic area than in other areas (ie, must be localized in appropriate areas), must be released by electrical or chemical stimulation via a calcium-dependent mechanism, and must produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse (ie, must exhibit synaptic mimicry). Table 21-2 lists the most important chemicals currently accepted as neurotransmitters in the CNS. 

Considering the chemical structure of ephedrine, it is interesting to observe the lack of the phenolic group, characteristic of catecholamines. However, ephedrine remains capable to stimulate a- and p-receptor directly and displace norepinephrine (NE) from storage vesicles, releasing these catecholamines at synaptic areas in the brain and in the heart. These released substances act on receptors promoting the adrenergic effect [17, 66]. 

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