Central nervous system amino acid neurotransmitters

A small subset of patients with hyperphenylalaninemia show an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) activity but have a deficiency in dihy-dropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydro-biopterin (BH4), a cofactor of PAH (see Fig. 39.18). Less frequently, DHPR activity is normal but a defect in the biosynthesis of BH4 exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, BH4 is also a cofactor for two other hydroxy-lations required in the synthesis of neurotransmitters in the brain the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa (see Chapter 48). It has been suggested that the resulting deficit in central nervous system neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

GABA (y-aminobutyric acid) is an amino acid with mostly inhibitory functions in the mammalian central nervous system. Structures involved in releasing or binding GABA as a neurotransmitter constitute the GABAergic system. The GABAergic system is involved... 

The amino acid glycine, a neurotransmitter at inhibitory synapses throughout the central nervous system (CNS),... 

The amino acid glutamate is the most widely used excitatory neurotransmitter in the central nervous system of mammals. Glutamate is the primary neurotransmitter used by the vast majority of reticular formation, thalamic and cortical neurons, which play a crucial role in the generation of the characteristic electrical activity as recorded in the electroencephalogram (for details see Steriade McCarley (2005)). The activity of these neurons is tightly regulated by the other neurotransmitters described in this chapter. 

The excitatoiy amino acids (EAA), glutamate and aspartate, are the principal excitatory neurotransmitters in the brain. They are released by neurons in several distinct anatomical pathways, such as corticofugal projections, but their distribution is practically ubiquitous in the central nervous system. There are both metabotropic and ionotropic EAA receptors. The metabotropic receptors bind glutamate and are labeled mGluRl to mGluRB. They are coupled via G-proteins to phosphoinositide hydrolysis, phospholipase D, and cAMP production. Ionotropic EAA receptors have been divided into three subtypes /V-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), and kainate receptors (Nakanishi 1992). 

Glycine is in a class by itself. It is the only protein amino acid that is not chiral. It is neither hydrophilic nor hydrophobic. With the exception of proline, all other protein amino acids are derived from it by substituting various groups on the oi carbon atom. Glycine is an important inhibitory neurotransmitter in the central nervous system. 

Glutamic add an amino acid commonly found in proteins and the most important excitatory neurotransmitter in the human central nervous system. 

There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

There are more than 10 billion neurons that make up the human nervous system, and they interact with one another through neurotransmitters. Acetylcholine, a number of biogenic amines (norepinephrine, dopamine, serotonin, and in all likelihood, histamine and norepinephrine), certain amino acids and peptides, and adenosine are neurotransmitters in the central nervous system. Amino acid neurotransmitters are glutamic and aspartic acids that excite postsynaptic membrane receptors of several neurons as well as y-aminobutyric acid (GABA) and glycine, which are inhibitory neurotransmitters. Endorphins, enkephalins, and substance P are considered peptidergic transmitters. There are many compounds that imitate the action of these neurotransmitters. 

Glutamic Acid A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. 

Glutamate (Glu) is the most abundant amino acid in the central nervous system (CNS). It serves many functions as an intermediate in neuronal metabolism, e.g., as a precursor for GABA. About 30% of the total glutamate in the brain functions as the major excitatory neurotransmitter. 

The amino acid L-glutamate is the main excitatory neurotransmitter of the central nervous system (Fonnum, 1984). Glutamate exerts its excitatory effects either by activation of several G-protein-coupled metabotropic glutamate receptors or by induction of ion fluxes by different classes of ionotropic receptors. The NMDA receptor is one of those glutamate-gated ion channels which got its name from its selective artificial agonist NMDA (N-methyl-D-aspartate) and which controls slow but persistent ion fluxes of Na+, K+, and Ca2+ across the cell membrane. 

Ketamine exerts its physiological effects at the molecular level by interfering with the actions of excitatory amino acid neurotransmitters, primarily glutamate, the most prevalent excitatory neurotransmitter in the brain. The excitatory neurotransmitters regulate numerous functions of the central nervous system. 

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. 

Aldridge and Reiner 1972). The A esterases have a serine catalytic site. The tertiary structure and amino acid sequences of several AChEs and BuChEs have been established (Taylor 1994). AChEs regulate excitation at cholinergic synapses, destroying the neurotransmitter ACh. AChE is one of the most active enzymes known, cycling within a few milliseconds (Taylor 1996). AChEs are found at synapses and neuromuscular junctions, and in central-nervous-system (CNS) neuron cell bodies, axons, muscles, red blood cells (RBCs), and platelets of ovine and rodent species (Silver 1974 Traina and Serpietri 1984 Hoffmann et al. 1989). 

---