Transmitter molecules

In contrast to the small transmitter molecules, the neuropeptides are synthesized in the rough endoplasmic reticulum of the neuronal perikarya. They are enclosed in vesicles in the Golgi apparatus. The vesicles travel down to the terminals by axonal transport. 

Walker, R.J., Brooks, H.L. and Holden-Dye, L. (1996) Evolution and overview of classical transmitter molecules and their receptors. Parasitology 113, S3-S34. 

Presynaptic vesicles are estimated to each contain approximately 3,000-5,000 transmitter molecules the internal volume of a vesicle is such that its internal transmitter concentration may be =0.5 mol/1 vesicle contents may be released within less than 1 ms and this occurs within <0.02 pm of the postsynaptic receptors. The space within... 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

The 1960 s and 1970 s saw several other hypotheses proposed and dis-proven. The monoamine oxidase (MAO) deficiency hypothesis was based on the observation of diminished activity of platelet MAO-B in schizophrenia, although this was likely to be an artifact of drug treatment and the small deficits could not, in any case, account for changes in monoamine transmitters. Other hypotheses relating to, among other transmitter molecules, noradrenaline and enkephalin/endorphin have also been proposed. Each of these have had propo-... 

Conduction of an action potential through the terminal branches of an axon causes depolarization of the varicosity membrane, resulting in the release of transmitter molecules via exocytosis. Once in the junctional extracellular space (biophase), acetylcholine interacts with cholinoreceptors. 

Reuptake. After the neurotransmitter is released, some chemical synapses terminate activity primarily by transmitter reuptake. Reuptake involves the movement of the transmitter molecule back into the presynaptic terminal. A drug that impairs the reuptake of transmitter allows more of it to remain in the synaptic cleft and continue to exert an effect. Consequently, blocking reuptake actually increases activity at the synapse. For instance, tricyclic antidepressants (see Chapter 7) impair the reuptake mechanism that pumps amine neurotransmitters back into the presynaptic terminal, which allows the transmitter to continue to exert its effect and prolong activity at the synapse. 

An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a safety valve to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. 

The message substances operating in neuroendocrine systems are amines, amino acids, acetylcholine and peptides. It should also be pointed out that our present understanding of neurotransmission in general may still be very limited, for according to Bloom 86, 87), in vertebrates at least, modern methods of chemical analysis are providing an ever-increasing list of new transmitter molecules . This situation is likely to be reflected in invertebrates also. 

Vesicular accumulation of catecholamines and of serotonin is inhibited by reserpine (Figure 10.14a). While reserpine initially was believed to inhibit the -ATP ase that generates and maintains a high proton concentration inside the vesicles , it is now clear that reserpine instead binds to the vesicular transmitter transporter that makes use of this proton gradient to move the transmitter uphill its own gradient into the vesicle (Figure 10.14b). The number of protons released for the import of each transmitter molecule is not known with certainty but is likely greater than 1. 

In addition to interfering with the reuptake of catecholamine transmitters, amphetamine will also release transmitter that is stored inside vesicles. This is different from reserpine, which only prevents uptake of more transmitter molecules into the vesicles but does not cause release of those already inside. The release itself can be demonstrated quite clearly with transmitter vesicles isolated form nerve tissue (Figure 10.17a) its mechanism, however, is still contentious. From several reports in the literature, 1 have distilled the modef depicted in Figure 10.17b. 

The existence of a curved conformation associated with the action potential is supported by the fact that the ion influx at the spike will induce an increased average wedge-shape of the molecules, due to electrostatic screening of the lateral repulsion of phosphatidylserine molecules. Furthermore a conformation associated with the spike would directly relate action potential propagation to the mass-cooperative vesicular fusion, involved in the chemical signal transfer by transmitter molecules at the pre-synaptic membrane. Experimental support for this concept has been recently reported [39]. This well-controlled fusion process of numerous "vesicles" with the presynaptic membrane must take place as a phase transition. The... 

The phenothiazine radical cations are particularly interesting because they have been implicated in charge transfer reactions with several neutral transmitter molecules (68) ... 

One process by which neurotransmitters are inactivated. Chemicals called enzymes interact with the transmitter molecule and change its structure so that it no longer is capable of occupying receptor sites. 

Cotransmitters Many (perhaps all) autonomic nerves have transmitter vesicles that contain other transmitter molecules in addition to the primary agents (ACh or NE) described above. These cotransmitters may be localized in the same vesicles as the primary transmitter or in a separate population of vesicles. Substances recognized to date as cotransmitters include ATP, enkephalins, vasoactive intestinal peptide (VIP), neuropeptide Y, substance P, neurotensin, somatostatin, and others. Their role in autonomic function appears to involve modulation of synaptic transmission. The same substances undoubtedly function as primary transmitters in other synapses. 

ACh release. According to the classical, vesicular hypothesis (Del Castillo Katz, 1954) packets of transmitter molecules ( quantums ) contained in synaptic vesicles are released by exocytosis. The vesicular hypothesis was in accordance with morphological studies demonstrating the existence of synaptic vesicles (De Roberties Bennett, 1954) and explained the discrete nature of the postsynaptic response, namely the occurrence of miniature-endplate potentials (Fatt Katz 1952). Alternative hypotheses (e.g. Israel Dunant, 1979 Tauc, 1979) are based on experimental observations of the release of cytoplasmic ACh. 

Many neurochemicals are stored usually in synaptic vesicles of the synapses. They may be released into the so-called synaptic clefts by an action potential [2]. In the synaptic cleft, transmitter molecules diffuse across the extracellular space... 

Repolarization of the post-synaptic membrane to a state of readiness for the next volley of transmitter molecules. 

Psychostimulant pharmacology involves an augmented release of noradrenaline and dopamine into the synaptic cleft. The presence of monoamine neurotransmitters in the synaptic cleft is regulated in a variety of ways in response to an action potential. Around 70-80% of all transmitter molecules return into the presynaptic neuron by uptake using an energy-dependent reuptake transport protein that is embedded in the neuronal membrane. A smaller fraction... 

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