Role as neurotransmitter

The principal hormones of the human posterior pituitary include the two nonapeptides, oxytocin [50-56-6] and arginine vasopressin [11000-17-2] (antidiuretic hormone, ADH). Many other hormones, including opioid peptides (see Opioids, endogenous), cholecystokinin [9011-97-6] (CCK) (see Hormones, BRAIN oligopeptides), and gastrointestinal peptides, also have been located in mammalian neurohypophysis (6), but are usually found in much lower concentrations (7). Studies have demonstrated that oxytocin and vasopressin are synthesized in other human organs, both centrally and peripherally, and there is considerable evidence for their role as neurotransmitters (see Neuroregulators) (8). 

As it is now clear that excitatory amino acids (EAA) play a critical role as neurotransmitters in the brain [279], in addition to the putative endogenous agonists, synthetic agonists such as NMDA 199 and (2J ,3S,4J )-a-(carboxycyclo-propyl)glycine 198 c have been identified, Eq. 79 [280]. 

A combination of decarboxylation and hydroxyla-tion of the ring of tyrosine produces derivatives of o-dihydroxybenzene (catechol), which play important roles as neurotransmitters and are also precursors to melanin, the black pigment of skin and hair. Catecholamines may be formed by decarboxylation of tyrosine into tyramine (step e, Fig. 25-5) and subsequent oxidation. However, the quantitatively more important route is hydroxylation by the reduced pterin-dependent tyrosine hydroxylase (Chapter 18) to 3,4-dihydroxyphenylalanine, better known as dopa. The latter is decarboxylated to dopamine.1313 Hydroxylation of dopamine by an ascorbic acid and... 

Acetylcholine seems the most widely distributed of the neurotransmitters in the c.n.s., and both muscarinic and nicotinic receptors have been recognized, the former being the more common (Kuhar, 1978). Three catecholamines (epinephrine, norepinephrine, and dopamine) also play important roles as neurotransmitters, each with its own system of nerves to operate on (Moore and Bloom, 1979). 5-Hydroxytryptamine 7.49) is an important transmitter in the midbrain and pons. 

If we now return to the question initially posed in this chapter is taurine a neurotransmitter , it emerges clearly that much more work is necessary before an adequate answer could be given. However, if we compare taurine responses with those of amino acids for which a role as neurotransmitter seems well established, like GABA or glycine, it seems that if taurine is actually acting as a synaptic transmitter, the extent of its involvement in such a role is rather restricted. Its neurophysiological action is weak, its release upon depolarization is controversial and probably calcium-independent and, most importantly, taurine postsynaptic receptors appear to be very scarce. Therefore, it may be considered that the main role of taurine in the CNS is not that of a neurotransmitter, althou such an action in restricted areas cannot be ruled out. 

As a neurotransmitter in the sensory nervous system, high levels of substance P are found in the dorsal horn of the spinal cord as well as in peripheral sensory nerve terminals. However, substance P also plays a significant role as a neuromodulator in the central, sympathetic, and enteric nervous system. NKA and NKB are also localized selectively in the CNS. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Histamine is synthesized from the amino acid histidine via the action of the specific enzyme histidine decarboxylase and can be metabolized by histamine-TV-methyl transferase or diamine oxidase. Interesting, in its role as a neurotransmitter the actions of histamine are terminated by metabolism rather than re-uptake into the pre-synaptic nerve terminals. 

Nonadrenergic noncholinergic inhibitory responses to autonomic nerve stimulation are mainly mediated through NO synthesized by nNOS NO plays a crucial role as a neurotransmitter from the peripheral efferent nerves, thus being called nitrergic. This provides a... 

AVP plays a central role in water homeostasis of terrestrial mammals, leading to water conservation by the kidney. OT is primarily involved in milk ejection, parturition and in sexual and maternal behaviour. Both hormones are pqDtides secreted by the neurohypophysis, and both act also as neurotransmitters in the central nervous system (CNS). The major hormonal targets for AVP are the renal tubules and vascular myocytes. The hormonal targets for OT are the myoepithelial cells... 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

There have been many references in this book to the role of neurotransmitters in the control of CNS excitability. It is therefore appropriate, but possibly foolhardy, to see if the two natural extremes of that excitability, namely sleep and waking, can be explained in terms of neurotransmitter activity. Of course, these states are not constant our sleep can be deep or light and, even when we are awake, our attention and vigilance fluctuate, as the reading of these pages will no doubt demonstrate. Also, the fact that we sleep does not mean that our neurotransmitters are inactive this would imply that sleep is a totally passive state, whereas all the evidence suggests that it is an actively induced process, subject to refined physiological control. 

Waagepetersen, H. S., Sonnewald, U., Schousboe, A. (1999) The GABA paradox multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent. J. Neurochem. 73, 1335-1342. 

Epinephrine is found only in very low concentrations in the mammalian CNS, and it is unlikely to play a major role as a neurotransmitter. 

In addition to its presumed role as a neurotransmitter within the brain, serotonin is synthesized in the pineal gland, where it is a precursor for the synthesis of melatonin, a hormone that influences endocrine activity, presumably by an action within the hypothalamus. 

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